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CN110234646B - Tau protein targeting PROTAC and related usage methods - Google Patents

Tau protein targeting PROTAC and related usage methods

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Publication number
CN110234646B
CN110234646B CN201780081243.4A CN201780081243A CN110234646B CN 110234646 B CN110234646 B CN 110234646B CN 201780081243 A CN201780081243 A CN 201780081243A CN 110234646 B CN110234646 B CN 110234646B
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optionally substituted
oxy
ulm
alkyl
pyrido
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CN110234646A (en
Inventor
安德鲁·P·克鲁
迈克尔·贝尔林
约翰·J·弗拉纳根
H·董
亚力克西·伊先科
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Arvinas Inc
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Arvinas Inc
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Abstract

The present disclosure relates to bifunctional compounds useful as modulators of tau protein. In particular, the present disclosure relates to bifunctional compounds containing a VHL or cereblon ligand on one end that binds to E3 ubiquitin ligase and a moiety on the other end that binds tau protein such that tau protein is placed in proximity to ubiquitin ligase to effect degradation (and inhibition) of tau. The present disclosure shows a broad range of pharmacological activities associated with degradation/inhibition of tau protein. Diseases or disorders arising from aggregation or accumulation of tau protein are treated or prevented with the compounds and compositions of the present disclosure.

Description

Tau protein targeting PROTAC and related methods of use
Cross Reference to Related Applications
The present disclosure claims priority from U.S. provisional application No. 62/415,830 filed on day 2016, 11, 1, which is incorporated herein by reference in its entirety.
Incorporated by reference
U.S. patent application Ser. No. 15/230,354, filed 8/5/2016, and U.S. patent application Ser. No. 62/406,888, filed 11/2016, and U.S. patent application Ser. No. 14/686,640, filed 4/14/2015, and U.S. patent application Ser. No. 14/792,414, filed 7/2015, 6, and U.S. patent application Ser. No. 14/371,956, filed 11/2014, and U.S. patent application Ser. No. 15/074,820, filed 18/2016, and filed 3/2016, respectively, disclosed as U.S. patent application publication No. 2014/0356322, and disclosed as U.S. patent application publication No. 2016/0272639, are incorporated herein by reference in their entirety. In addition, all references cited herein are incorporated by reference in their entirety.
Background
1. Technical field
The present description relates to bifunctional compounds useful for modifying intracellular ubiquitination and subsequent degradation of target polypeptides and proteins, particularly Tau proteins. The compounds of the present disclosure place the target protein/polypeptide in proximity to ubiquitin ligase to effect ubiquitination and degradation (and inhibition) of Tau protein.
2. Background art
Most small molecule drugs bind enzymes or receptors in tightly and well-defined pockets. On the other hand, protein-protein interactions are notoriously difficult to target with small molecules due to their large contact surface and the shallow or flat interfaces involved. E3 ubiquitin ligases, hundreds of which are known in humans, confer substrate specificity for ubiquitination and, therefore, are more attractive therapeutic targets than general proteasome inhibitors due to their specificity for certain protein substrates. The development of E3 ligase ligands has proven challenging, in part, due to the fact that they must disrupt protein-protein interactions. Recent developments, however, have provided specific ligands that bind to these ligases. For example, since the discovery of the first small molecule E3 ligase inhibitor nutlin, additional compounds targeting E3 ligase have been reported, but this field is still under development.
One E3 ligase with exciting therapeutic potential is von Hippel-Lindau (VHL) tumor suppressor, the substrate recognition subunit of the E3 ligase complex VCB, which also consists of extension proteins B and C, cul and Rbx 1. The primary substrate for VHL is hypoxia-inducible factor 1 alpha (HIF-1 alpha), a transcription factor that responds to hypoxia-level up-regulated genes such as the angiogenic growth factor VEGF and the erythrocyte-inducing cytokine erythropoietin. The first small molecule ligand of von Hippel-Lindau (VHL) directed against the substrate recognition subunit of E3 ligase was generated and a crystal structure was obtained, confirming that this compound mimics the binding pattern of the transcription factor HIF-1 a (the major substrate of VHL).
Cereblon is a protein encoded by CRBN gene in human. CRBN orthologs are highly conserved from plant to human, emphasizing their physiological importance. Cereblon form an E3 ubiquitin ligase complex with impaired DNA binding protein 1 (DDB 1), cullin-4A (CUL 4A) and CUllin modulator 1 (ROC 1). This complex ubiquitinates many other proteins. By a mechanism that has not been fully elucidated, cereblon ubiquitination of target proteins results in increased levels of fibroblast growth factor 8 (FGF 8) and fibroblast growth factor 10 (FGF 10). FGF8 in turn regulates many developmental processes such as limb and auditory bulb formation. The net result is that this ubiquitin ligase complex is important for limb growth in the embryo. In the absence of cereblon, DDB1 forms a complex with DDB2, which DDB2 acts as a DNA-damage binding protein.
Tau protein is a rich protein in the central nervous system found mainly in neuronal cells, although Tau is expressed at lower levels in other cells of the central nervous system. In healthy neurons, tau binds to microtubules and modulates microtubule stability, which is critical for axon growth and neuron plasticity. When pathologically altered, tau molecules are unable to stabilize microtubules and are prone to form insoluble aggregates. Once Tau protein forms insoluble aggregates in cells, cellular dysfunction occurs, axonal transport is impaired, and neuronal loss follows. The accumulation of abnormal Tau aggregates in neurons is an important pathological feature of a variety of neurodegenerative disorders, including alzheimer's disease. Under certain pathological conditions, tau aggregation results in double helix filaments (PHF), straight Filaments (SF) and/or neurofibrillary tangles (NFT). The accumulation of PHF and NFT in neurons is directly associated with microtubule dysfunction and neuronal degeneration. Neurons containing tau PHF, SF and or NFT activate different cellular mechanisms to attempt to remove abnormal protein aggregates in cells.
More recent studies suggest that instead of large insoluble filaments, soluble Tau oligomers may play a more critical role in the onset and progression of disease before PHF or NFT induced neurotoxicity develops. The oligomeric species of Tau can act as seeds for natural Tau aggregation, thereby promoting neurotoxic Tau aggregation. Accumulated evidence has suggested that Tau aggregates can be transmitted from one cell to another in a prion-like manner.
Tau alterations and dysfunction and extensive neuronal loss have long been associated with several neurodegenerative diseases (now collectively referred to as tauopathies).
The term "tauopathic" or "tauopathy (tauopathies)" refers herein to a class of neurodegenerative diseases associated with pathological aggregation of Tau protein in neurofibrils or glial fibrillary tangles in the human brain. Examples of tauopathies include, but are not limited to, AD, down syndrome, frontotemporal lobular dementia (FTLD), cotricobasal degeneration (CBD), and Progressive Supranuclear Palsy (PSP)
Tau is an important therapeutic target due to its pathological significance in a variety of neurodegenerative diseases. Prevention of Tau aggregation becomes a potential strategy for treating neurodegenerative disorders associated with Tau. To date, great efforts have been made to identify the molecular mechanisms of Tau aggregation and to find therapeutic agents to stop the progression of neurodegeneration.
Tau aggregation inhibitors demonstrating promising preclinical data have proven ineffective in recent clinical trials for the treatment of various Tau lesions. Thus, there is a need in the art for effective treatment of diseases and conditions associated with Tau aggregation in neurodegenerative disorders such as tauopathies.
Disclosure of Invention
The present disclosure describes bifunctional compounds, including compositions comprising the same, that act to recruit endogenous proteins to E3 ubiquitin ligases for ubiquitination and subsequent degradation, and methods of use thereof. In particular, the present disclosure provides bifunctional or proteolytic targeted chimeric (PROTAC) compounds that are useful as modulators of targeted ubiquitination and Tau protein aggregate degradation. In addition, the present specification provides methods for treating or ameliorating a disease condition, such as tauopathy, due to accumulation or aggregation of Tau protein using an effective amount of a compound as described herein. Such diseases or conditions include, but are not limited to, neurological conditions or neurodegenerative conditions.
Thus, in one aspect, the present disclosure provides compounds that act to recruit endogenous proteins (e.g., tau) to the E3 ubiquitin ligase for ubiquitination and degradation.
In any embodiment, the compound has the general structure
PTM-L-ULM
In certain embodiments, the compounds have the general structure (A)
PTM-L-VLM (A)
In certain embodiments, the compounds have the general structure (B)
PTM-L-CLM (B)
Wherein PTM represents a protein targeting moiety, ULM represents an E3 ubiquitin ligase targeting moiety including, but not limited to, VLM (VHL ligase binding moiety) and CLM (cereblon ligase binding moiety), and L represents a linker, such as a bond or a chemical linker moiety. As will be appreciated by those skilled in the art, difunctional compounds as described herein may be synthesized such that the number and location of the individual functional moieties may be varied as desired.
In certain embodiments, the PTM in structure (a) is a ligand that binds Tau as well as VHL E3 ubiquitin ligase.
In certain embodiments, the PTM in structure (B) is a ligand that binds Tau as well as CLM E3 ubiquitin ligase.
In certain embodiments, a compound as described herein comprises a plurality of ULMs, a plurality of PTMs, a plurality of chemical linkers, or a combination thereof. In another aspect, the present specification provides a therapeutic composition comprising an effective amount of a compound as described herein or a salt form thereof and a pharmaceutically acceptable carrier. The therapeutic compositions modulate protein degradation in a patient or subject (e.g., an animal, such as a human), and may be used to treat or ameliorate a disease state or condition modulated by the degraded protein. In certain embodiments, therapeutic compositions as described herein may be used to effect degradation of a protein of interest for treating or ameliorating a disease, such as a neuronal disease. In yet another aspect, the present disclosure provides methods of ubiquitinating/degrading a target protein in a cell. In certain embodiments, the method comprises administering a bifunctional compound as described herein comprising ULM and PTM, which can be linked by a linker moiety, as described elsewhere herein, wherein ULM is coupled to PTM and wherein ULM recognizes ubiquitin pathway proteins, such as ubiquitin ligases, e.g., E3 ubiquitin ligases, more preferably VLM and CLM, and PTM recognizes target proteins (TBM), such that when a target protein (e.g., tau) is placed in proximity to ubiquitin ligases, degradation of the target protein will occur, thus resulting in degradation of the target protein, inhibition of its effect, and control of protein levels. In another aspect, the target protein is Tau. The present disclosure provides treatment of disease states or conditions that are controlled by protein levels, i.e., by reducing the level of a protein (e.g., tau protein) in a patient's cells via degradation.
In particular, PTM is a molecule that binds to the Tau protein (TBM), and ULM is a molecule that binds to VHL E3 ubiquitin ligase and/or CLM E3 ubiquitin ligase, having the general structure:
TBM-L-VLM/CLM
the PTM (protein targeting moiety) of PROTAC of the present disclosure is represented by the general formulae I, II, III, IV, V, VI, VII, VIII, XI, X and XI:
wherein:
A. B, C, D, E and F are each independently selected from optionally substituted 5 or 6 membered aryl or heteroaryl rings, optionally substituted 4 to 7 membered cycloalkyl or heterocycloalkyl, wherein contact between the circles indicates ring fusion, and
L PTM is selected from a bond, alkyl, alkenyl, or alkynyl, optionally interrupted by one or more rings (i.e., cycloalkyl, heterocycloalkyl, aryl, or heteroaryl), or one or more functional groups, which may include-O-, -S-, -NR 1 PTM - (wherein R 1 PTM is selected from H or alkyl )、-N＝N-、-S(O)-、-SO2-、-C(O)-、-NHC(O)-、-C(O)NH-、-NHSO2-、-NHC(O)NH-、-NHC(O)O-、-OC(O)NH-, wherein the functional groups may optionally be located at either end of the linker (i.e., directly adjacent to the A, B, C, D, E or F ring).
The above aryl and heteroaryl rings may be optionally substituted with 1 to 3 substituents each independently selected from the group consisting of alkyl, alkenyl, haloalkyl, halogen, hydroxy, alkoxy, fluoroalkoxy, amino, alkylamino, dialkylamino, amido, trifluoromethyl and cyano, wherein the alkyl and alkenyl groups may be further substituted.
In any aspect or embodiment described herein, at least one of A, B, C, F or a combination thereof is selected from an optionally substituted 5 or 6 membered aryl or heteroaryl ring.
In certain embodiments of the present disclosure, PTM is represented by formula I and/or II, wherein A, B and C are 5 or 6 membered fused aryl or heteroaryl rings, L PTM is selected from a bond or alkyl, and D is selected from 6 membered aryl, heteroaryl, or heterocycloalkyl, wherein A, B, C and D are optionally substituted with alkyl, haloalkyl, halogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, trifluoromethyl, or cyano.
In other embodiments, PTM is represented by formula III and/or IV, wherein A, B and C are 5 or 6 membered fused aryl or heteroaryl rings, L PTM is selected from a bond or alkyl, and D and E are 5 or 6 membered fused aryl or heteroaryl rings, and wherein A, B, C, D and E are optionally substituted with alkyl, haloalkyl, halogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, trifluoromethyl, or cyano.
In certain other embodiments of the present disclosure, PTM is represented by formula I, wherein a is phenyl or a 6 membered heteroaryl ring, B is a 5 membered heteroaryl ring, C is phenyl or a 6 membered heteroaryl ring, L PTM is a bond, and D is a 6 membered heteroaryl or 6 membered heterocycloalkyl ring, wherein each A, B, C and D is optionally independently substituted with alkyl, haloalkyl, halogen, hydroxy, alkoxy, amino, dialkylamino, trifluoromethyl, or cyano, with the proviso that none of the nitrogen atoms of any of the A, B, C and D rings are directly connected to a heteroatom or carbon atom of LPTM, and the other heteroatom is directly attached to the L PTM.
It should be understood that the general structure is exemplary and that the various portions may be spatially arranged in any desired order, number, or configuration.
In further embodiments, the present description provides bifunctional compounds having a structure selected from compounds 1-330 (e.g., compounds selected from tables 1 and 2), salts, polymorphs, and prodrugs thereof.
In further embodiments, the present specification provides bifunctional compounds having a structure selected from table 1 or table 2 (e.g., a chemical structure selected from compounds 1-330), salts, polymorphs, and prodrugs thereof.
In another aspect, the present specification provides a composition comprising a compound as described herein and a pharmaceutically acceptable carrier. In certain embodiments, the composition is a therapeutic or pharmaceutical composition comprising an effective amount of a compound as described herein and a pharmaceutically acceptable carrier. In certain embodiments, the therapeutic or pharmaceutical composition comprises an additional bioactive agent, e.g., an agent effective for treating a neuronal disorder.
In any aspect or embodiment described herein, the therapeutic composition comprising the compounds described herein may be in any suitable dosage form, e.g., solid or liquid, and configured for delivery by any suitable route, e.g., oral, parenteral, intravenous, intraperitoneal, subcutaneous, intramuscular, etc.
In another aspect, the present specification provides a method of modulating Tau protein, ubiquitination and subsequent degradation thereof in a subject (e.g., a cell, tissue, mammal, or human patient), comprising administering to the subject an effective amount of a compound as described herein or a composition comprising an effective amount thereof, wherein the compound or composition comprising the same is effective to modulate Tau ubiquitination and degradation in the subject.
In yet another aspect, the present specification provides a method of treating or ameliorating a symptom of a disease associated with TAU activity in a subject (e.g., a cell, tissue, mammal, or human patient), the method comprising administering to a subject in need thereof an effective amount of a compound as described herein or a composition comprising the same, wherein the compound or composition comprising the same is effective to treat or ameliorate a symptom of a disease associated with TAU activity in a subject. In certain embodiments, the disease to be treated is a neurological disease or neurodegenerative disease, such as alzheimer's, parkinson's, dementia, and the like.
In a preferred embodiment, the subject is a human.
In yet another aspect, the present disclosure provides methods for identifying the effects of degradation of a protein of interest in a biological system using a compound according to the present disclosure.
Any one embodiment described herein is contemplated to be able to be combined with any other embodiment or embodiments, where applicable or not specifically stated, even though the embodiments are described under different aspects of the present disclosure. As such, the foregoing general field of use is given by way of example only and is not intended to limit the scope of the present disclosure and appended claims. Further objects and advantages associated with the compositions, methods and methods of the present disclosure will be apparent to those of ordinary skill in the art from the claims, specification and examples. For example, the various aspects and embodiments of the disclosure may be utilized in numerous combinations, all of which are explicitly contemplated by the present specification. These additional advantages, objects, and embodiments are expressly included within the scope of the present disclosure. Publications and other materials used herein to illuminate the background of the disclosure and, in particular instances, to provide additional details respecting the practice, are incorporated by reference.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the disclosure and together with the description, serve to explain the principles of the disclosure. The drawings are only for purposes of illustrating embodiments of the disclosure and are not to be construed as limiting the disclosure. Further objects, features and advantages of the present disclosure will become apparent from the following detailed description when taken in conjunction with the accompanying drawings, which show illustrative embodiments of the present disclosure, wherein:
Figure 1 shows total tau levels in hippocampal homogenates. The data are shown as a scatter plot. Statistically significant differences between the Test Item (TI) treated groups versus the vehicle control groups are indicated by asterisks p <0.01, p <0.05 according to one-way ANOVA followed by Dunneett multiple comparison tests.
Detailed Description
The following is a detailed description provided to assist those skilled in the art in practicing the disclosure. Modifications and variations may be made in the embodiments described herein by those of ordinary skill in the art without departing from the spirit or scope of the present disclosure. All publications, patent applications, patents, figures, and other references mentioned herein are expressly incorporated by reference in their entirety.
The present specification relates to the surprising and unexpected discovery that once an E3 ubiquitin ligase protein and a target protein are accessed by a chimeric construct (e.g., PROTAC) as described herein, the E3 ubiquitin ligase protein can ubiquitinate the target protein, the chimeric construct binds to the E3 ubiquitin ligase protein (e.g., VHL and cereblon) and the target protein, e.g., TAU. Accordingly, the present specification provides compounds, compositions comprising the same, and related methods of use for ubiquitination and degradation of selected target proteins.
The following terms are used to describe the present disclosure. Where a term is not specifically defined herein, that term is given its art-recognized meaning to be used by a person of ordinary skill in the context of describing its use in this disclosure.
Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit, unless the context clearly dictates otherwise (e.g., where a group contains multiple carbon atoms, each carbon atom number falling within that range is provided), between the upper and lower limit of that range, and any other stated or intervening value in that stated range, is encompassed within the disclosure. The upper and lower limits of these smaller ranges, which may independently be included in the smaller ranges, are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either of those two limits are also included in the disclosure.
The articles "a" and "an" as used herein and in the appended claims are used herein to refer to one or more than one (i.e., to at least one) of the grammatical object of the article unless the context clearly dictates otherwise. For example, "an element" means one element or more than one element.
As used herein in the specification and claims, the phrase "and/or" should be understood to mean "either or both" of the elements so combined, i.e., elements that in some cases exist in combination and in other cases exist separately. A plurality of elements listed as "and/or" should be interpreted in the same manner, i.e., as "one or more" elements so combined. In addition to the elements specifically identified by the "and/or" clause, other elements may optionally be present, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to "a and/or B" when used in conjunction with an open language such as "comprising" can refer to only a (optionally including elements other than B) in one embodiment, to only B (optionally including elements other than a) in another embodiment, to both a and B (optionally including other elements) in yet another embodiment, and so forth.
As used herein in the specification and claims, "or" should be understood to have the same meaning as "and/or" as defined above. For example, when items in a list are separated, "or" and/or "should be construed as inclusive, i.e., including at least one, but also including more than one of many elements or lists of elements, and optionally, additional unlisted items. Only the opposite terms, such as "only one" or "exactly one," or when used in a claim, "consisting of" means exactly one element of a number or list of elements. In general, when preceded by an exclusive term such as "either," "one," "only one," or "exactly one," as used herein, the term "or" should be interpreted to indicate only an exclusive alternative (i.e., "one or the other but not both").
In the claims and in the above description, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," "making up," and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" should be closed or semi-closed transitional phrases, respectively, as described in section 2111.03 of the United states patent office patent review program manual (United STATES PATENT Office Manual of Patent Examining Procedures).
As used herein in the specification and claims, references to a list of one or more elements, the phrase "at least one" should be understood to mean at least one element selected from any one or more elements in the list of elements, but not necessarily including each and at least one of each element specifically listed in the list of elements, and not excluding any combination of elements in the list of elements. The definition also allows that in addition to elements specifically identified within the list of elements referred to by the phrase "at least one," there may optionally be elements whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, "at least one of A and B" (or equivalently, "at least one of A or B," or equivalently "at least one of A and/or B") may refer, in one embodiment, to at least one, optionally including more than one, A, and optionally including elements other than B, in another embodiment, to at least one, optionally including more than one, and optionally including elements other than A, and in yet another embodiment, to at least one, optionally including more than one, and at least one, optionally including more than one, B (and optionally including other elements), and the like.
It should also be understood that in some methods described herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited, unless the context indicates otherwise.
As used herein, unless otherwise indicated, the term "compound" refers to any particular compound disclosed herein and includes tautomers, regioisomers, geometric isomers and applicable stereoisomers thereof, including optical isomers (enantiomers) and other stereoisomers (diastereomers), as well as pharmaceutically acceptable salts and derivatives (including prodrug forms) thereof, as applicable in the context. Within its context, the term compound generally refers to a single compound, but may also include other compounds, such as stereoisomers, regioisomers and/or optical isomers (including racemic mixtures), as well as specific enantiomers or enantiomerically enriched mixtures of the disclosed compounds. In this context, the term also refers to a prodrug form of a compound that has been modified to facilitate the administration and delivery of the compound to an active site. It should be noted that in describing the compounds herein, a number of substituents and variables associated therewith are described, inter alia. The skilled artisan will appreciate that the molecules described herein are stable compounds as generally described below.
When the key is displayedWhen double bonds and single bonds are both represented in the context of the compounds shown.
The term "patient" or "subject" is used throughout the specification to describe an animal, preferably a human or domestic animal, to which treatment, including prophylactic treatment, is provided with a composition according to the present disclosure. For the treatment of those infections, conditions or disease states that are specific to a particular animal (e.g., a human patient), the term patient refers to that particular animal, including domestic animals such as dogs or cats or farm animals such as horses, cattle, sheep, etc. Generally, in this disclosure, the term patient refers to a human patient unless otherwise indicated or implied by the context in which the term is used.
The term "effective" is used to describe an amount of a compound, composition, or component that, when used in the context of its intended use, achieves the intended result. The term effective encompasses all other effective amounts or effective concentration terms that are otherwise described or used in this patent application.
The term "ubiquitin ligase" refers to a family of proteins that promote the transfer of ubiquitin to a specific substrate protein, targeting the substrate protein for degradation. For example, cereblon is an E3 ubiquitin ligase protein, alone or in combination with an E2 ubiquitin conjugating enzyme, causes attachment of ubiquitin to lysine on the target protein, and subsequently targets specific protein substrates for degradation by the proteasome. Thus, the E3 ubiquitin ligase alone or in complex with the E2 ubiquitin conjugating enzyme is responsible for the transfer of ubiquitin to the target protein. Generally speaking, ubiquitin ligases are involved in polyubiquitination such that a second ubiquitin is attached to a first ubiquitin, a third ubiquitin is attached to a second ubiquitin, and so on. Polyubiquitination labels proteins for degradation by proteasome. However, there are some ubiquitination events, which are limited to monoubiquitination, where only a single ubiquitin is added to the substrate molecule by ubiquitin ligases. Monoubiquitinated proteins are not targeted to proteasome for degradation, but rather may be altered in their cellular location or function, for example, via binding to other proteins having domains capable of binding ubiquitin. More complex, different lysines of ubiquitin can be targeted by E3 to make chains. The most common lysine is Lys48 on the ubiquitin chain. This is lysine used to prepare polyubiquitin recognized by the proteasome.
The term "protein target moiety" or PTM is used to describe a small molecule that binds to a target protein or other protein or polypeptide of interest and places/exists the protein or polypeptide in proximity to ubiquitin ligase such that degradation of the protein or polypeptide by ubiquitin ligase can occur. Non-limiting examples of small molecule target protein binding moieties include compounds that target Tau proteins.
The term "target protein" is used to describe a protein or polypeptide, which is a target for binding a compound according to the present disclosure and degradation by ubiquitin ligase below. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target the protein of interest. These binding moieties are linked to the ULM groups through linker groups L.
Tau protein targets can be used in screens to identify portions of a compound that bind to a protein, and by incorporating the portions into a compound according to the present disclosure, the level of activity of the protein can be altered for treatment of the end result.
The term "disease state or condition" is used to describe any disease state or condition in which a protein imbalance occurs (i.e., the amount of protein expressed in a patient is increased), and in which degradation of Tau protein in a patient can provide beneficial therapy or relief of symptoms to a patient in need thereof. In some cases, the disease state or condition may be cured.
Disease states or conditions that may be treated using compounds according to the present disclosure include neuronal diseases such as neurodegeneration, huntington's disease and muscular dystrophy, parkinson's disease, alzheimer's disease, babbitt disease, spinal cord and brain injury, epilepsy, brain tumors, meningitis, autoimmune diseases such as multiple sclerosis, neurofibromatosis, depression, amyotrophic lateral sclerosis, arteriovenous malformations, cerebral aneurysms, dural arteriovenous fistulae, headaches, memory disorders, peripheral neuropathy, post-herpetic neuralgia, spinal cord tumors, stroke.
As used herein, the term "neurological disorder (neurological disorder)" or "neurological disorder (neurological disorders)" refers to any disorder, disease, and/or syndrome due to or resulting from neurological, psychiatric, psychological, and/or cerebrovascular symptomatology or origin. As used herein, the term "neurological disorder (neurological disorder)" or "neurological disorder (neurological disorders)" also refers to a disease, disorder or condition of the brain and nervous system or a psychotic disorder or condition. Neurological disorders including, but not limited to, clear-stop, acquired epileptic-like aphasia, acute disseminated encephalomyelitis, ADHD, addison's pupil, addison's syndrome, adrenoleukodystrophy, callosity dysplasia, agnosia, ekadi syndrome, AIDS-neurological complications, alexander's disease, alter's disease, alternant hemiplegia, alzheimer's disease, amyotrophic lateral sclerosis, brain deformity, aneurysms, angel's syndrome, angiomatosis, hypoxia, aphasia, disuse, arachnoid cyst, arachnoiditis, alzhi, arteriovenous malformations, abbe's syndrome, ataxia, alzheimers disease, aldrich's disease, ataxia, telangiectasia, ataxia and cerebellar/spinal cerebellar degeneration, attention deficit hyperactivity disorder, autism, autonomic dysfunction, back pain, papanic syndrome, barbillosis, becky's muscle rigidity, behcet's disease, bell palsy, benign essential blepharospasm, benign focal amyotrophy, benign intracranial hypertension, ber-Luo Ershi syndrome, bischwann disease, blepharospasm, bush-Su Ershi syndrome, brachial plexus injury, brachial plexus nerve injury, bragg-Eggeston syndrome, brain and spinal tumors, cerebral aneurysms, brain injury, brown-Szechter syndrome, bulbar amyotrophy, karnwann disease, carpal tunnel syndrome causalgia, spongiform tumor, spongiform hemangioma, spongiform vascular malformation, central cervical syndrome, central cord syndrome, central pain syndrome, cranial disorders, cerebellar degeneration, cerebellar hypoplasia, cerebral aneurysm, cerebral arteriosclerosis, brain atrophy, cerebral beriberi, cerebral giant, cerebral anoxia, cerebral palsy, brain-eye-face-bone syndrome, summer-horse-figure three disease, chiari malformation, chorea acanthocytosis, chronic Inflammatory Demyelinating Polyneuropathy (CIDP), chronic erectile intolerance type II chronic pain cocaine syndrome, ke-le two syndrome, COFS, cavitary brain, coma and persistent plant states, complex regional pain syndrome, congenital facial paralysis, congenital muscle weakness, congenital myopathy, congenital spongiform vessels, deformity, corticobasal degeneration, craniarteritis, craniosynostosis, creutzfeldt-jakob disease, cumulative trauma disorder, cushing's syndrome, giant cell inclusion body disease, cytomegalovirus infection, chorea of the eye, dan-Wo Ershi syndrome, morse, demuxia syndrome, deep brain stimulation of parkinson's disease, dejerine-Klumpke paralysis, dementia-multiple cerebral infarctions, dementia-semanticance, dementia-subcortical, subcortical pain, Dementia with lewy bodies, dentate nucleus cerebellar ataxia, dentate nucleus erythronuclear atrophy, dermatomyositis, developmental dyskinesia, devickers syndrome, diabetic neuropathy, diffuse sclerosis, familial autonomic nerve abnormalities, dyskinesia, cerebellar dyssynergia, myoclonus, progressive cerebellar dyssynergia, dystonia, early stage infant epilepsy, encephalopathy, jetlag syndrome, comatose encephalitis, brain swelling, encephalopathy, cerebral trigeminal angiomatosis, epilepsy, erb-Duchenne and Dejerine-Klumpke paralysis, european-Behcet's paralysis, fabry's disease, French syndrome, syncope, familial autonomic dysfunction, familial hemangioma, familial idiopathic basal ganglia calcification, familial periodic paralysis, familial spastic paralysis, febrile convulsion, fisher syndrome, sonchus infant syndrome, friedel-crafts ataxia, frontotemporal dementia, gaucher's disease, gettman syndrome, gekko Shi Xiesan disease, giant cell arteritis, giant cell inclusion body disease, leukodystrophy, glossopharyngalgia, geobanches syndrome, hash's disease, head injury, headache, persistent migraine, hemifacial spasm, hemiplegia Alterans, hereditary neuropathy, Hereditary spastic paraplegia, hereditary ataxia polyneuritis, shingles, ping Shan syndrome, hodgher's syndrome, forebrain crazy deformity, HTLV-1 related myelopathy, huntington's disease, water retention cerebral deformity, hydrocephalus-normal pressure, hydrocephalus, hyperkinesia, hypercortisolism, hypersomnia, hypotonia-infant, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, pigment incontinence, hypotonia of infant, infantile nerve axonal dystrophy, infant phytanic acid storage disease, infant Lei Fusu m disease, infantile cramps, inflammatory myopathy, Occipital split cerebral dew deformity, intestinal lipodystrophy, intracranial cysts, intracranial hypertension, isaacs syndrome, zhu Bate syndrome, kennel-Sachs syndrome, kennedy's disease, kingbriner's syndrome, kernel-Living syndrome, kernel-Fei Ershi syndrome, kernel-Techner's syndrome (KTS), kernel-Buddy's syndrome, kosakoff forgetting syndrome, kerabe disease, cookawer's disease, kuru, landau-Airy's muscle weakness syndrome, landau-Klefner syndrome, lateral femoral, cutaneous nerve entrapment, bulbar lateral syndrome, learning disorders, lei's disease, lei-Goos syndrome, lei-Nardy's syndrome, Leukodystrophy, levine-CRITCHLEY syndrome, lewy body dementia, lipid storage disorder, cerebral palsy, atresia syndrome, gray's disease, lupus-neurology, sequelae, lyme disease-neurological complications, equine-Johnson's disease, megabrain, mania, megabrain, michelia-Luo Ershi syndrome, meningitis and encephalitis, mentha's disease, paresthesia femoral pain, metachromatic, leukodystrophy, microcephaly, migraine, millefre's syndrome, small stroke, mitochondrial myopathy, morbites syndrome, single limb atrophy, motor neuron disease, smogopathy, mucolipidosis, Mucopolysaccharidoses, multifocal motor neuropathy, multi-infarct dementia, multiple sclerosis, multiple system atrophy with orthostatic hypotension, muscular dystrophy, muscle weakness-congenital, myasthenia gravis, demyelinating diffuse sclerosis, infant myoclonus encephalopathy, myoclonus, myopathy-congenital, myopathy-thyrotoxicosis, myotonia, congenital myotonia, narcolepsy, acanthocytosis, neurodegenerative disorders with brain iron deposition, neurofibromatosis, nerve blocker malignancy, neurological complications of AIDS, neurological complications of lyme disease, neurological consequences of cytomegalovirus infection, Neurological manifestations of pompe disease, neurological sequelae of lupus, neuromyelitis optica, neuromyotonia, neuronal ceroid, lipofuscinosis, neuronal migration disorders, neuropathy-hereditary, neurosarcoidosis, neurotoxicity, moles cavernosum, niemann-pick disease, normal pressure hydrocephalus, occipital neuralgia, obesity, recessive spinal neural tube insufficiency sequences, dada syndrome, olivopontocerebellar atrophy, strabismus-clonus myoclonus, orthostatic hypotension, O' Sullivan-McLeod syndrome, overuse syndrome, pain-chronic, pain, pantothenate kinase-related neurodegeneration, Paraneoplastic syndrome, paresthesia, parkinson's disease, paroxysmal chorea athetosis, paroxysmal migraine, parry-Romberg, pet-Mei-two's disease, pena Shokeir II syndrome, nerve bundle cyst, periodic paralysis, peripheral neuropathy, periventricular leukomalacia, persistent plant status, pervasive developmental disorder, phytanic acid storage disease, pick's disease, neuromarking, piriform muscle syndrome, pituitary tumor, polymyositis, pompe disease, pornoglos, postherpetic neuralgia, post-infection encephalomyelitis, post-poliomyelitis syndrome, orthostatic hypotension, Tachycardia syndrome, postural tachycardia syndrome, primary Dentatum atrophy, primary lateral sclerosis, primary progressive aphasia, prion diseases, progressive hemifacial atrophy, progressive motor ataxia, progressive multifocal, leukoencephalopathy, progressive sclerosing gray matter dystrophy, progressive supranuclear, paralysis, face-unknown, pseudoencephaloma, lambdazin hunter syndrome I (previously known), lambdazin hunter syndrome II (previously known), rasmussen encephalitis, reflex sympathetic dystrophy syndrome, lei Fusu m disease, lei Fusu m disease-infancy, repetitive movement disorder, Repetitive stress injury, restless leg syndrome, retrovirus-associated spinal cord disease, rate's syndrome, rayleigh-Dai Ershi syndrome, sacral nerve root cyst, saint Vitex's chorea, salivary gland disease, mordeHough's disease, shebrew's disease, cerebral fissure, saint Begonia disease, epilepsy, semantic dementia, dysplasia of the visual-septa type, infant swing syndrome, SHINGLES SHY-Drager syndrome, sjogren's syndrome, sleep apnea, comatose, sotos syndrome, spasticity, spinal column fissure, spinal infarction, spinal cord injury, spinal cord tumor, spinal muscular atrophy, spinal cerebellar atrophy, Spinocerebellar, degenerative, sri-Otts syndrome, stiff person syndrome, striatal degeneration, stroke, sri-Weber syndrome, subacute sclerotic encephalitis, subcortical arteriosclerotic encephalopathy, SUNCT headache dysphagia, west Duham chorea, syncope, syphilitic myelosclerosis, syringohol's disease, systemic lupus erythematosus, phthisis tardive dyskinesia, tarlov cyst, tarlov-Satwo's disease, temporal arteritis, spinal cord embolic syndrome, thomsen's myotonic, chest outlet syndrome, thyrotoxicosis, trigeminal neuralgia, todder paralysis, tourette syndrome, transient ischemic attacks, transmissible spongiform encephalopathy, transverse myelitis, traumatic brain injury, tremor, trigeminal neuralgia, tropical spastic lower limb paralysis, nodular sclerosis, vascular erectile tumors, vasculitis including temporal arteritis, embopogon disease, hill-Lin's disease (VHL), feng Leike Lin Huozeng's disease, walen Bei Geshi syndrome, wer-Huo Ershi disease, west syndrome, whiplash syndrome, hupler's disease, williams syndrome, wilson's disease, X-linked spinal bulbar atrophy or Zellweger syndrome.
The term "bioactive agent" is used to describe an agent other than a compound according to the present disclosure that is used in combination with a compound of the present disclosure as a bioactive agent to help achieve the desired therapy, inhibition, and/or prevention/prophylaxis for its use of the compound herein.
Where applicable, the term "pharmaceutically acceptable salt" is used throughout the specification to describe salt forms of one or more compounds described herein, which are used to increase the solubility of the compound in gastric juice of the gastrointestinal tract of a patient, so as to promote dissolution and bioavailability of the compound. Where applicable, pharmaceutically acceptable salts include salts derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium, magnesium and ammonium salts, and numerous other acids and bases well known in the pharmaceutical arts. Sodium and potassium salts are particularly preferred as the neutralized salts of the phosphates according to the present disclosure.
The term "pharmaceutically acceptable derivative" is used throughout the specification to describe any pharmaceutically acceptable prodrug form (e.g., ester, amide, other prodrug group) that, when administered to a patient, directly or indirectly provides the compound herein or an active metabolite of the compound herein.
The term "independently" is used herein to indicate that the variables of an independent application change independently from application to application.
The term "hydrocarbyl" shall mean compounds containing carbon and hydrogen and which may be fully saturated, partially unsaturated or aromatic, and include aryl, alkyl, alkenyl and alkynyl groups.
The term "alkyl" shall mean in this context a straight, branched or cyclic fully saturated hydrocarbon radical or alkyl, preferably C 1-C10, more preferably C 1-C6, alternatively C 1-C3 alkyl, which may be optionally substituted. Examples of alkyl are in particular methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methylpropyl, cyclopropyl-methyl, cyclobutyl, cyclopentyl, cyclopentylethyl, cyclohexylethyl and cyclohexyl.
The term "lower alkyl" means an alkyl group having no more than six carbon atoms.
The term "unsubstituted" shall mean substituted with only hydrogen atoms. The carbon atom range including C 0 means that carbon is absent and that the substitution is H. Thus, the carbon atom range for C 0-C6 includes 1, 2,3, 4, 5, and 6 carbon atoms, and for C 0, H replaces carbon. The term "substituted" or "optionally substituted" shall mean independently (i.e., when more than one substituent is present, each substituent is independent of the other substituent) one or more substituents at carbon (or nitrogen) positions anywhere on the molecule within the context (independently up to five substituents, preferably up to three substituents, often 1 or 2 substituents, and may include substituents that may themselves be further substituted, on part of a compound according to the present disclosure), and includes hydroxy, thiol, carboxyl, cyano (c≡n), nitro (NO 2), Halogen (preferably 1,2 or 3 halogen, especially alkyl, especially methyl such as trifluoromethyl), alkyl (preferably C 1-C10, more preferably C 1-C6), aryl (especially phenyl and substituted phenyl, such as benzyl or benzoyl), alkoxy (preferably C 1-C6 alkyl or aryl, including phenyl and substituted phenyl), Thioether (C 1-C6 alkyl or aryl), acyl (preferably C 1-C6 acyl), Esters or thioesters (preferably C 1-C6 alkyl or aryl) include alkylene esters (such that the attachment is to an alkylene group, rather than at the ester functionality, which is preferably substituted with a C 1-C6 alkyl or aryl group), preferably a C 1-C6 alkyl or aryl group, Halogen (preferably F or Cl), An amine (including five or six membered cyclic alkylene amines, also including C 1-C6 alkyl amines or C 1-C6 dialkyl amines, the alkyl groups may be substituted with one or two hydroxy groups) or an optionally substituted-N (C 0-C6 alkyl) C (O) (O-C 1-C6 alkyl) group (which may be optionally further substituted with a polyethylene glycol chain to which an alkyl group containing a single halogen, preferably chlorine, substituent is further bonded), hydrazine, amido, which is preferably substituted with one or two C 1-C6 alkyl groups (including formamide optionally substituted with one or two C 1-C6 alkyl groups), alkanols (preferably C 1-C6 alkyl or aryl groups), or alkanoic acids (preferably C 1-C6 alkyl or aryl groups) as substituents. substituents according to the present disclosure may include, for example, a —sir 1R2R3 group, where R 1 and R 2 are each as described elsewhere herein, and R 3 is H or C 1-C6 alkyl, in this context preferably R 1、R2、R3 is C 1-C3 alkyl (including isopropyl or tert-butyl). Each of the above groups may be directly attached to a substituted moiety, or alternatively, a substituent may be attached to a substituted moiety (preferably in the case of an aryl or heteroaryl moiety) through an optionally substituted- (CH 2)m -or alternatively an optionally substituted- (OCH 2)m-、-(OCH2CH2)m -or- (CH 2CH2O)m -group, which may be substituted with any one or more of the above substituents). As identified above, the alkylene- (CH 2)m -or- (CH 2)n -group) or other chain such as ethylene glycol chain may be substituted anywhere on the chain. Preferred substituents on the alkylene group include halogen or C 1-C6 (preferably C 1-C3) alkyl which may optionally be substituted with one or two hydroxy groups, one or two ether groups (O-C 1-C6 groups), up to three halogen groups (preferably F), or side chains of amino acids as described elsewhere herein and optionally substituted amides (preferably substituted carboxamides as described above) or carbamate groups (often having one or two C 0-C6 alkyl substituents which may be further substituted). In certain embodiments, the alkylene (often a single methylene) is substituted with one or two optionally substituted C 1-C6 alkyl groups, preferably C 1-C4 alkyl groups, most often methyl or O-methyl groups, or the side chains of amino acids as described elsewhere herein. In the present disclosure, a moiety in a molecule may optionally be substituted with up to five substituents, preferably up to three substituents. most often, in the present disclosure, the substituted moiety is substituted with one or two substituents.
The term "substituted" (each substituent independent of any other substituent) shall also mean in the context of its use C 1-C6 alkyl, C 1-C6 alkoxy, halogen, amido, carboxamido, sulfone including sulfonamide, keto, carboxyl, C 1-C6 ester (oxy ester or carbonyl ester), c 1-C6 Keto, carbamate-O-C (O) -NR 1R2 or-N (R 1)-C(O)-O-R1, nitro, cyano and amine (including especially C 1-C6 alkylene-NR 1R2), mono-or di-C 1-C6 alkyl-substituted amines, which may optionally be substituted with one or two hydroxy groups). Within the context, each of these groups contains from 1 to 6 carbon atoms unless otherwise indicated. In certain embodiments, preferred substituents include, for example, -NH-, -NHC (O) -, -O-, = O, - (CH 2)m - (where m and n are 1, 2,3, 4, 5 or 6) in the context of, -S-, -S (O) -, SO 2 -or –NH-C(O)-NH-、-(CH2)nOH、-(CH2)nSH、-(CH2)nCOOH、C1-C6 alkyl, - (CH 2)nO-(C1-C6 alkyl), - (CH 2)nC(O)-(C1-C6 alkyl), - (CH 2)nOC(O)-(C1-C6 alkyl), - (CH 2)nC(O)O-(C1-C6 alkyl )、-(CH2)nNHC(O)-R1、-(CH2)nC(O)-NR1R2、-(OCH2)nOH、-(CH2O)nCOOH、C1-C6 alkyl), - (OCH 2)nO-(C1-C6 alkyl), - (CH 2O)nC(O)-(C1-C6 alkyl )、-(OCH2)nNHC(O)-R1、-(CH2O)nC(O)-NR1R2、-S(O)2-RS、-S(O)-RS(RS is C 1-C6 alkyl or- (CH 2)m-NR1R2 group), NO 2, CN or halogen (F, cl, br, I, preferably F or Cl), depending on the context in which the substituents are used. Within the context, R 1 and R 2 are each H or C 1-C6 alkyl (which may optionally be substituted by one or two hydroxy groups or up to three halogen groups, preferably fluorine). Within the chemical context of the defined compounds and substituents used, the term "substituted" shall also mean optionally substituted aryl or heteroaryl or optionally substituted heterocyclyl as described elsewhere herein. alkylene groups may also be substituted, preferably with optionally substituted C 1-C6 alkyl groups (methyl, ethyl or hydroxymethyl or hydroxyethyl groups are preferred, thus providing chiral centers), side chains of amino acid groups as described elsewhere herein, amide groups as described above, or carbamate O-C (O) -NR 1R2 groups where R 1 and R 2 are described elsewhere herein, although numerous other groups may also be used as substituents. The various optionally substituted moieties may be substituted with 3 or more substituents, preferably no more than 3 substituents, preferably 1 or 2 substituents. It should be noted that in the case where a compound at a particular position of a molecular substitution is desired (mainly due to potency) but no substitution is indicated, the substituent is interpreted or understood as H unless the context of substitution suggests that this is not the case.
In this context, the term "aryl" or "aromatic" refers to an unsubstituted monovalent aromatic radical substituted (as described elsewhere herein) or having a single ring (e.g., benzene, phenyl, benzyl) or condensed rings (e.g., naphthyl, anthryl, phenanthryl, etc.), and may be bound to a compound according to the present disclosure at any available stable position on the ring or as otherwise indicated in the chemical structure presented. In this context, other examples of aryl groups may include heterocyclic aromatic ring system "heteroaryl" groups, which have one or more nitrogen, oxygen or sulfur atoms, especially in a ring (monocyclic) such as imidazole, furyl, pyrrole, furyl, thiophene, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole or fused ring systems such as indole, quinoline, indolizine, azaindolizine, benzofurazan, and the like, which may optionally be substituted as described above. Among the heteroaryl groups which may be mentioned are nitrogen-containing heteroaryl groups, such as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indolizine, azaindolizine, purine, indazole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinolizine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazoline,Pyridine, phenanthroline, phenanthrene (phenacene), oxadiazole, benzimidazole, pyrrolopyridine, pyrrolopyrimidine and pyridopyrimidine, sulfur-containing aromatic heterocycles such as thiophene and benzothiophene, oxygen-containing aromatic heterocycles such as furan, pyran, cyclopentapyran, benzofuran and isobenzofuran, and aromatic heterocycles containing 2 or more heteroatoms selected from nitrogen, sulfur and oxygen, such as thiazole, thiadiazole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole, phenothiazine, isoxazole, furazan, phenoxazine, pyrazolooxazole, imidazothiazole, thienofuran, furopyrrole, pyrrolizine, furopyridine, furopyrimidine, thienopyrimidine and oxazole, all of which may be optionally substituted.
The term "heterocycle" refers to a cyclic group that contains at least one heteroatom, O, N or S, and may be aromatic (heteroaryl) or non-aromatic. Thus, depending on the context in which it is used, heteroaryl moieties are included under the definition of heterocycle. Exemplary heteroaryl groups are described above. Exemplary non-aromatic heterocyclic groups for use in the present disclosure include, for example, pyrrolidinyl, pyrrolinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, tetrahydropyranyl, azetidinyl, oxetanyl, oxathiolanyl, pyridone, 2-pyrrolidone, ethyleneurea, 1, 3-dioxolane, 1, 3-dioxane, 1, 4-dioxane, phthalimide, and succinimide, among others.
The term "co-administration" or "combination therapy" shall mean that at least two compounds or compositions are administered to a patient simultaneously, such that an effective amount or concentration of each of the two or more compounds can be found in the patient at a given point in time. Although compounds according to the present disclosure may be co-administered to a patient at the same time, the term includes administration of two or more agents at the same time or at different times, provided that the effective concentration of all co-administered compounds or compositions is found in the subject at a given time. In certain preferred aspects of the present disclosure, one or more of the compounds described herein are co-administered in combination with at least one additional bioactive agent, including, inter alia, anticancer agents. In particular aspects of the disclosure, co-administration of the compounds results in synergistic treatment, including anti-cancer therapies
The present disclosure describes bifunctional compounds and methods of use thereof that act to recruit endogenous proteins to the E3 ubiquitin ligase for degradation. In particular, the present disclosure provides bifunctional or proteolytic targeted chimeric (PROTAC) compounds that are useful as modulators of targeted ubiquitination of Tau proteins. The compounds provided herein have the advantage that a broad range of pharmacological activities are possible, consistent with degradation/inhibition of Tau protein.
As such, the present disclosure provides such compounds and compositions comprising an E3 ubiquitin ligase targeting moiety ("ULM") coupled to a Tau protein target binding moiety ("PTM") that results in ubiquitination of the Tau protein, which results in degradation (and/or inhibition) of the Tau protein. The disclosure also provides libraries of compositions and uses thereof.
The present specification provides compounds comprising a ligand, e.g., a small molecule ligand (i.e., having a molecular weight of less than 2,000, 1,000, 500 or 200 daltons), which is capable of binding ubiquitin ligases, e.g., VHL or cereblon. The compound further comprises a moiety capable of binding to the target protein in such a way that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and/or inhibition) of the protein. In addition to the above, a small molecule may also mean that the molecule is non-peptidyl, i.e. it is generally not considered a peptide, e.g. comprising less than 4, 3 or 2 amino acids. According to the present specification, the PTM, ULM or PROTAC molecule may be a small molecule.
In one embodiment, the present specification provides a composition for modulating protein activity. The composition comprises a ubiquitin pathway protein binding moiety (preferably for VHL or cereblon) and a Tau protein targeting moiety according to a defined chemical structure, preferably linked together by a linker, wherein the ubiquitin pathway protein binding moiety recognizes ubiquitin pathway protein and the targeting moiety recognizes Tau target protein, and wherein the ubiquitin pathway protein binding moiety is coupled to the Tau targeting moiety.
In another embodiment, the present disclosure provides a library of compounds. The library comprises more than one compound, wherein each composition has an ubiquitin pathway protein binding moiety (preferably VHL or cereblon) and a Tau protein binding moiety, wherein ULM is coupled (preferably via a linker moiety) to Tau, and wherein the ubiquitin pathway protein binding moiety recognizes ubiquitin pathway proteins, in particular E3 ubiquitin ligase.
In another embodiment, the present disclosure provides methods of ubiquitinating/degrading a target protein (e.g., tau) in a cell. The method comprises administering a bifunctional composition comprising a ubiquitin pathway protein binding moiety and a targeting moiety, as described elsewhere herein, preferably linked by a linker moiety, wherein the ubiquitin pathway protein binding moiety is coupled to the targeting moiety, and wherein the chromophore ubiquitin pathway protein binding moiety recognizes the ubiquitin pathway protein (e.g. VHL, cereblon) and the targeting moiety recognizes the target protein (e.g. Tau) such that when the target protein is placed in proximity to ubiquitin ligase, degradation of the target protein will occur, thus leading to inhibition of degradation/effect of the target protein and control of protein levels. The control of protein levels provided by the present disclosure provides for the treatment of disease states or conditions that are modulated by target proteins by reducing the levels of the protein in patient cells.
In yet another embodiment, the present disclosure relates to a method of treating a patient in need of treatment for a disease state or condition modulated by a protein (e.g., tau), wherein degradation of the protein results in a therapeutic effect in the patient, comprising administering to the patient in need thereof an effective amount of a compound according to the present disclosure, optionally in combination with another bioactive agent. The disease state or condition may be a disease caused by a microbial agent or other exogenous agent (e.g., a virus, bacterium, fungus, protozoan, or other microorganism), or may be a disease state caused by overexpression of a protein, i.e., accumulation or aggregation of Tau protein, which results in a disease state and/or condition.
In one aspect, the present disclosure provides compounds for modulating protein activity. The composition comprises an E3 ubiquitin ligase, an ubiquitin pathway protein binding moiety and a protein targeting moiety, preferably linked or coupled together by a linker, wherein the ubiquitin pathway protein binding moiety recognizes the ubiquitin pathway protein and the targeting moiety recognizes a target protein (e.g., tau). Such compounds may be referred to herein as PROTAC compounds or PROTAC, having the general chemical structure:
ULM―L―PTM,
or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or prodrug thereof,
Wherein ULM is a small molecule E3 ubiquitin ligase binding moiety that binds E3 ubiquitin ligase;
PTM is a small molecule comprising a Tau protein targeting moiety which degrades the Tau protein, and
L is a bond or a chemical linking moiety linking ULM and PTM.
In certain embodiments, the E3 ubiquitin ligase binding moiety targets a member of the group consisting of Von Hippel-Lindau (VLM), cereblon (CLM), mouse double-micro homolog 2 (MLM), and IAP (ILM).
In one aspect, the present description provides Tau protein binding moieties (PTMs). In certain embodiments, PTM is represented by formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, or formula XI:
wherein:
A. b, C, D, E and F are independently selected from optionally substituted 5 or 6 membered aryl or heteroaryl rings, optionally substituted 4 to 7 membered cycloalkyl or heterocycloalkyl, wherein contact between the circles indicates ring fusion, and
L PTM is selected from a bond, alkyl, alkenyl or alkynyl, optionally interrupted by one or more rings (i.e. cycloalkyl, heterocycloalkyl, aryl or heteroaryl), or one or more functional groups selected from-O-, -S-, -NR 1 PTM - (wherein R 1 PTM is selected from H or alkyl), -n=n-, -S (O) -, -SO 2-、-C(O)-、-NHC(O)-、-C(O)NH-、-NHSO2 -, -NHC (O) NH-, -NHC (O) O-, or-OC (O) NH-, wherein the functional groups are optionally located at either end of the linker.
In certain embodiments, the aryl and heteroaryl rings of A, B, C, D, E and F of PTM are optionally substituted with 1-3 substituents each independently selected from the group consisting of alkyl, alkenyl, haloalkyl, halogen, hydroxy, alkoxy, fluoroalkoxy, amino, alkylamino, dialkylamino, amido, trifluoromethyl and cyano, wherein the alkyl and alkenyl are further optionally substituted.
In certain embodiments, the ring of at least one of A, B, C, F or a combination thereof is selected from optionally substituted 5 or 6 membered aryl or heteroaryl rings;
in certain embodiments, the PTM has the chemical structure of formula I, wherein:
A. the B and C rings are independently 5 or 6 membered fused aryl or heteroaryl rings;
L PTM is selected from a bond or alkyl, and
D is selected from 6-membered aryl, heteroaryl or heterocycloalkyl,
Wherein A, B, C and D are optionally substituted with alkyl, haloalkyl, halogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, or cyano.
In certain further embodiments, the PTM has the chemical structure of formula I, wherein:
a and C are phenyl or 6 membered heteroaryl rings;
b is a 5 membered heteroaryl ring;
l PTM is a bond, and
D is a6 membered heteroaryl or 6 membered heterocycloalkyl ring;
Wherein each A, B, C and D is optionally independently substituted with alkyl, haloalkyl, halogen, hydroxy, alkoxy, amino, dialkylamino, or cyano, and wherein the nitrogen atom of any of the A, B, C and D rings is not directly attached to a heteroatom or carbon atom to which the other heteroatom is directly attached.
In other embodiments, the PTM has a chemical structure of formula III or IV, wherein A, B and C are 5 or 6 membered fused aryl or heteroaryl rings, L PTM is selected from a bond or alkyl, and D and E are 5 or 6 membered fused aryl or heteroaryl rings, wherein A, B, C, D and E are optionally substituted with alkyl, haloalkyl, halogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, or cyano.
In certain embodiments, the PTM is represented by the following chemical structure:
wherein:
R 1、R2 and R 3 are independently selected from H, methyl, ethyl, 2-fluoroethyl and 2, 2-trifluoroethyl;
R 4 and R 5 are independently selected from H, methyl, ethyl and halogen, and
R 6 is 1 to 2 substituents independently selected from H, methyl, ethyl and halogen,
Wherein PTM is coupled to ULM via L.
In any aspect or embodiment described herein, the PTM is covalently coupled to one or more ULM (VLM or CLM) groups or a linker to which one or more ULM (VLM or CLM) groups are attached as described herein.
In certain embodiments, the PTM is represented by the following chemical structure:
wherein:
r 1、R2 and R 3 are independently selected from H, optionally substituted alkyl, methyl, ethyl, 2-fluoroethyl and 2, 2-trifluoroethyl, and
R 7、R8、R9 and R 10 are 1 to 8 substituents independently selected from H, optionally substituted alkyl, haloalkyl, halogen, hydroxy, alkoxy, amino, dialkylamino, acetamido, trifluoromethyl or cyano, and wherein PTM is coupled to ULM (VLM or CLM) via L.
In certain further embodiments, the PTM is represented by the following chemical structure:
in certain embodiments, the joint attachment point to the PTM is as shown by the dashed line:
Exemplary VLM:
in one aspect, the ULM is VHL.
In certain embodiments of the compounds as described herein, the ULM is a VLM and comprises a chemical structure selected from ULM-a:
wherein:
Wherein the dashed line indicates the attachment of at least one PTM, another ULM or VLM or CLM (i.e. ULM 'or VLM' or CLM '), or a chemical linker moiety coupling at least one PTM, ULM' or VLM 'or CLM' with the other end of the linker;
Each X 1、X2 is independently selected from the group consisting of a bond, O, NR Y3、CRY3RY4, c= O, C =s, SO, and SO 2;
each R Y3、RY4 is independently selected from H, linear or branched C 1-6 alkyl optionally substituted with 1 or more halogens, C 1-6 alkoxy);
r P is 1,2, or 3 groups, each independently selected from H, halogen, -OH, C 1-3 alkyl;
W 3 is selected from optionally substituted-T-N (R 1aR1b), optionally substituted-T-N (R 1aR1b)X3, -T-aryl, optionally substituted-T-heteroaryl, optionally substituted-T-heterocycle, optionally substituted-NR 1 -T-aryl, optionally substituted-NR 1 -T-heteroaryl or optionally substituted-NR 1 -T-heterocycle;
X 3 is c= O, R 1、R1a、R1b
R 1、R1a、R1b are each independently selected from H, linear or branched C 1-C6 alkyl 、RY3C＝O、RY3C＝S、RY3SO、RY3SO2、N(RY3RY4)C＝O、N(RY3RY4)C＝S、N(RY3RY4)SO optionally substituted with 1 or more halogen or-OH groups, and N (R Y3RY4)SO2;
wherein T is covalently bonded to X1;
W 4 is optionally substituted-NR 1-T-aryl, optionally substituted-NR 1-T-heteroaryl or optionally substituted-NR 1-T-heterocycle, wherein-NR 1 is covalently bonded to X2 and R1 is H or CH3, preferably H.
In any of the embodiments described herein, T is selected from optionally substituted alkyl, - (CH 2)n -groups, wherein each of the methylene groups is optionally substituted with one or two substituents selected from halogen, methyl, straight or branched C 1-C6 alkyl optionally substituted with 1 or more halogen or-OH groups, or optionally substituted amino acid side chains, and
N is 0 to 6, frequently 0, 1, 2 or 3, preferably 0 or 1.
In certain embodiments, W 4 is Wherein R 14a、R14b, each independently is selected from H, haloalkyl or optionally substituted alkyl;
In any aspect or embodiment described herein, W 5 is selected from phenyl or 5-10 membered heteroaryl,
R 15 is selected from H, optionally substituted alkyl of halogen 、CN、OH、NO2、N R14aR14b、OR14a、CONR14aR14b、NR14aCOR14b、SO2NR14aR14b、NR14a SO2R14b、, optionally substituted haloalkyl, optionally substituted haloalkoxy, aryl, heteroaryl, cycloalkyl or cycloheteroalkyl;
In further embodiments, the W 4 substituents used in the present disclosure also specifically include (and are not limited to) the W 4 substituents found in the identified compounds disclosed herein. Each of these W 4 substituents may be used in combination with any number of W 3 substituents also disclosed herein.
In certain additional embodiments, ULM- α is optionally substituted with 1-3R P groups in the pyrrolidine moiety. Each R P is independently H, halogen, -OH, C1-3 alkyl.
In any of the embodiments described herein, W 3、W4 can be independently covalently coupled to a linker to which one or more PTM groups are attached.
And wherein the dashed line indicates the attachment site of at least one PTM, another ULM (ULM '), or a chemical linker moiety coupling at least one PTM or ULM', or both, to the ULM.
In certain embodiments, the ULM is VHL and is represented by the following structure:
wherein:
W 3 is selected from optionally substituted aryl, optionally substituted heteroaryl, or
R 9 and R 10 are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl, or R 9、R10 and the carbon atom to which they are attached form optionally substituted cycloalkyl;
r 11 is selected from optionally substituted heterocycle, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl,
R 12 is selected from H or optionally substituted alkyl;
R 13 is selected from H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl) alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl) carbonyl or optionally substituted aralkyl;
r 14a、R14b, each independently selected from H, haloalkyl or optionally substituted alkyl;
W 5 is selected from phenyl or 5-10 membered heteroaryl,
R 15 is selected from H, optionally substituted alkyl of halogen 、CN、OH、NO2、N R14aR14b、OR14a、CONR14aR14b、NR14aCOR14b、SO2NR14aR14b、NR14a SO2R14b、, optionally substituted haloalkyl, optionally substituted haloalkoxy, aryl, heteroaryl, cycloalkyl or cycloheteroalkyl (each independently optionally substituted);
R 16 is independently selected from H, halogen, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or optionally substituted haloalkoxy;
o is 0,1, 2, 3 or 4;
R 18 is independently selected from halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy, or linker, and
P is 0, 1, 2, 3 or 4, and wherein the dashed line indicates the attachment site of at least one PTM, another ULM (ULM '), or a chemical linker moiety coupling at least one PTM or ULM', or both, to the ULM.
In certain embodiments, R 15 isWherein R 17 is H, halogen, optionally substituted C 3-6 cycloalkyl, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkenyl and C 1-6 haloalkyl, and Xa is S or O.
In certain embodiments, R 17 is selected from methyl, ethyl, isopropyl, and cyclopropyl.
In certain further embodiments, R 15 is selected from:
in certain embodiments, R 11 is selected from:
in certain embodiments, the ULM has a chemical structure selected from the group consisting of:
wherein:
R 1 is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
R 14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl or cyclopropyl;
R 15 is selected from H, halogen, CN, OH, NO 2, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, cycloalkyl or cycloheteroalkyl;
X is C, CH 2 or c=o
R 3 is a bond or an optionally substituted 5-or 6-membered heteroaryl, and
Wherein the dashed line indicates the attachment site of at least one PTM, another ULM (ULM '), or a chemical linker moiety coupling at least one PTM or ULM', or both, to ULM (ULM-a).
In certain embodiments, the ULM comprises groups according to the following chemical structure:
wherein:
R 14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl or cyclopropyl;
R 9 is H;
r 10 is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
R11 is
Or optionally substituted heteroaryl;
p is 0,1, 2, 3 or 4;
each R 18 is independently halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy, or linker;
R12 is H, C =o;
R13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl) alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl) carbonyl or optionally substituted aralkyl,
R 15 is selected from H, halogen, cl, CN, OH, NO 2, optionally substituted heteroaryl, optionally substituted aryl;
Wherein the dashed line indicates the attachment site of at least one PTM, another ULM (ULM '), or a chemical linker moiety coupling at least one PTM or ULM', or both, to the ULM.
In certain embodiments, the ULM is selected from the following structures:
wherein n is 0 or 1.
In certain embodiments, the ULM is selected from the following structures:
Wherein the benzene rings in ULM-a1 to ULM-a15, ULM-b1 to ULM-b12, ULM-c1 to ULM-c15 and ULM-d1 to ULM-d9 are optionally substituted with fluorine, lower alkyl and alkoxy groups, and wherein the dashed lines indicate the attachment sites of at least one PTM, another ULM (ULM ') or a chemical linker moiety coupling at least one PTM or ULM' or both with ULM-a.
In one embodiment, the benzene rings in ULM-a1 through ULM-a15, ULM-b1 through ULM-b12, ULM-c1 through ULM-c15, and ULM-d1 through ULM-d9 may be functionalized as esters so that they become part of the prodrug.
In certain embodiments, the hydroxyl groups on the pyrrolidine ring of ULM-a1 to ULM-a15, ULM-b1 to ULM-b12, ULM-c1 to ULM-c15, and ULM-d1 to ULM-d9, respectively, comprise an ester-linked prodrug moiety.
In any aspect or embodiment described herein, the ULM and the present ULM' are each independently a group according to the chemical structure:
wherein:
R 1' of ULM-g is optionally substituted C 1-C6 alkyl, optionally substituted- (CH 2)n OH), optionally substituted- (CH 2)n SH), Optionally substituted (CH 2)nO-(C1-C6) alkyl, optionally substituted (CH 2)n-WCOCW-(C0-C6) alkyl containing epoxide moiety WCOCW (wherein each W is independently H or C 1-C3 alkyl), optionally substituted- (CH 2)n COOH), Optionally substituted- (CH 2)nC(O)-(C1-C6 alkyl), optionally substituted- (CH 2)nNHC(O)-R1, optionally substituted- (CH 2)nC(O)-NR1R2), optionally substituted- (CH 2)nOC(O)-NR1R2、-(CH2O)n H), Optionally substituted- (CH 2)nOC(O)-(C1-C6 alkyl), optionally substituted- (CH 2)nC(O)-O-(C1-C6 alkyl)), optionally substituted- (CH 2O)n COOH, optionally substituted- (OCH 2)nO-(C1-C6 alkyl), Optionally substituted- (CH 2O)nC(O)-(C1-C6 alkyl), optionally substituted- (OCH 2)nNHC(O)-R1, optionally substituted- (CH 2O)nC(O)-NR1R2、-(CH2CH2O)n H), optionally substituted- (CH 2CH2O)n COOH), Optionally substituted- (OCH 2CH2)nO-(C1-C6 alkyl), optionally substituted- (CH 2CH2O)nC(O)-(C1-C6 alkyl), optionally substituted- (OCH 2CH2)nNHC(O)-R1, optionally substituted- (CH 2CH2O)nC(O)-NR1R2), Optionally substituted-SO 2RS, optionally substituted S (O) R S、NO2, CN or halogen (F, cl, br, I, preferably F or Cl);
R 1 and R 2 of ULM-g are each independently H or C 1-C6 alkyl, which may optionally be substituted by one or two hydroxy groups or up to three halogen groups (preferably fluorine);
R S of ULM-g is C 1-C6 alkyl, optionally substituted aryl, heteroaryl or heterocyclyl or a- (CH 2)mNR1R2 group;
Each of X and X 'of ULM-g is independently c= O, C =s, -S (O), S (O) 2, (preferably X and X' are both c=o);
R 2' of ULM-g is an optionally substituted- (CH 2)n-(C＝O)u(NR1)v(SO2)w alkyl group, an optionally substituted –(CH2)n-(C＝O)u(NR1)v(SO2)wNR1NR2N group, an optionally substituted- (CH 2)n-(C＝O)u(NR1)v(SO2)w -aryl group, an optionally substituted- (CH 2)n-(C＝O)u(NR1)v(SO2)w -heteroaryl group), an optionally substituted- (CH 2)n-(C＝O)vNR1(SO2)w -heterocycle) optionally substituted-NR 1-(CH2)n-C(O)u(NR1)v(SO2)w -alkyl, optionally substituted -NR1-(CH2)n-C(O)u(NR1)v(SO2)w-NR1NR2N、 optionally substituted -NR1-(CH2)n-C(O)u(NR1)v(SO2)w-NR1C(O)R1N、 optionally substituted-NR 1-(CH2)n-(C＝O)u(NR1)v(SO2)w -aryl, optionally substituted-NR 1-(CH2)n-(C＝O)u(NR1)v(SO2)w -heteroaryl or optionally substituted-NR 1-(CH2)n-(C＝O)vNR1(SO2)w -heterocycle, optionally substituted-X R2' -alkyl; optionally substituted-X R2' -aryl, -optionally substituted-X R2' -heteroaryl, -optionally substituted-X R2' -heterocyclyl;
R 3' of ULM-g is optionally substituted alkyl, optionally substituted- (CH 2)n-(O)u(NR1)v(SO2)w -alkyl), Optionally substituted –(CH2)n-C(O)u(NR1)v(SO2)w-NR1NR2N、 optionally substituted –(CH2)n-C(O)u(NR1)v(SO2)w-NR1C(O)R1N、 optionally substituted –(CH2)n-C(O)u(NR1)v(SO2)w-C(O)NR1R2、 optionally substituted- (CH 2)n-C(O)u(NR1)v(SO2)w -aryl), Optionally substituted- (CH 2)n-C(O)u(NR1)v(SO2)w -heteroaryl), optionally substituted- (CH 2)n-C(O)u(NR1)v(SO2)w -heterocycle, optionally substituted-NR 1-(CH2)n-C(O)u(NR1)v(SO2)w -alkyl, optionally substituted -NR1-(CH2)n-C(O)u(NR1)v(SO2)w-NR1NR2N、 optionally substituted -NR1-(CH2)n-C(O)u(NR1)v(SO2)w-NR1C(O)R1N、 optionally substituted-NR 1-(CH2)n-C(O)u(NR1)v(SO2)w -aryl, Optionally substituted-NR 1-(CH2)n-C(O)u(NR1)v(SO2)w -heteroaryl, optionally substituted-NR 1-(CH2)n-C(O)u(NR1)v(SO2)w -heterocycle, optionally substituted-O- (CH 2)n-(C＝O)u(NR1)v(SO2)w -alkyl, optionally substituted-O- (CH 2)n-(C＝O)u(NR1)v(SO2)w-NR1NR2N), Optionally substituted -O-(CH2)n-(C＝O)u(NR1)v(SO2)w-NR1C(O)R1N、 optionally substituted-O- (CH 2)n-(C＝O)u(NR1)v(SO2)w -aryl, optionally substituted-O- (CH 2)n-(C＝O)u(NR1)v(SO2)w -heteroaryl) or optionally substituted-O- (CH 2)n-(C＝O)u(NR1)v(SO2)w -heterocycle; a- (CH 2)n-(V)n'-(CH2)n-(V)n' -alkyl group), An optionally substituted- (CH 2)n-(V)n'-(CH2)n-(V)n' -aryl group), an optionally substituted- (CH 2)n-(V)n'-(CH2)n-(V)n' -heteroaryl group, an optionally substituted- (CH 2)n-(V)n'-(CH2)n-(V)n' -heterocyclic' group), an optionally substituted- (CH 2)n-N(R1')(C＝O)m'-(V)n' -alkyl group, An optionally substituted- (CH 2)n-N(R1')(C＝O)m'-(V)n' -aryl group, an optionally substituted- (CH 2)n-N(R1')(C＝O)m'-(V)n' -heteroaryl group), an optionally substituted- (CH 2)n-N(R1')(C＝O)m'-(V)n' -heterocyclic group), Optionally substituted-X R3' -alkyl group, -optionally substituted-X R3' -aryl group, -optionally substituted-X R3' -heteroaryl group, -optionally substituted-X R3' -heterocyclic group;
R 1N and R 2N of ULM-g are each independently H, C 1-C6 alkyl optionally substituted with one or two hydroxy groups and up to three halogen groups, or optionally substituted- (CH 2)n -aryl, - (CH 2)n -heteroaryl or- (CH 2)n -heterocyclyl);
ULM-g V is O, S or NR 1;
R 1 of ULM-g is the same as above;
r 1 and R 1' of ULM-g are each independently H or C 1-C3 alkyl;
ULM-g X R2' and X R3' are each independently optionally substituted-CH 2)n-、–CH2)n-CH(Xv)＝CH(Xv) - (cis or trans), -CH 2)n-CH≡CH-、-(CH2CH2O)n -, or C 3-C6 cycloalkyl, wherein X v is H, halogen, or optionally substituted C 1-C3 alkyl;
each m of ULM-g is independently 0, 1, 2,3, 4, 5, 6;
each m' of ULM-g is independently 0 or 1;
Each n of ULM-g is independently 0, 1, 2,3, 4, 5, 6;
each n' of ULM-g is independently 0 or 1;
each u of ULM-g is independently 0 or 1;
each v of ULM-g is independently 0 or 1;
Each w of ULM-g is independently 0 or 1, and
Any one or more of R 1'、R2'、R3', X, and X ' of ULM-g is optionally modified to covalently bond to a PTM group through a linker group when PTM is not ULM ', or any one or more of R 1'、R2'、R3', X, and X ' of each of ULM and ULM ' is optionally modified to covalently bond to each other directly or through a linker group when PTM is ULM ', or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof.
In any aspect or embodiment described herein, the ULM and the present ULM' are each independently a group according to the chemical structure:
wherein:
Each of R 1'、R2' and R 3' of ULM-h is the same as above, and X is a c= O, C =s, -S (O) group or S (O) 2 group, more preferably a c=o group, and
Optionally modifying any one or more of R 1'、R2' and R 3' of ULM-h to bind a linker group that is further covalently bonded to the PTM group when PTM is not ULM ', or optionally modifying one or more of R 1'、R2'、R3' of each of ULM and ULM ' to be covalently bonded to each other directly or through the linker group when PTM is ULM ', or
Pharmaceutically acceptable salts, enantiomers, diastereomers, solvates or polymorphs thereof.
In any aspect or embodiment described herein, the ULM and the present ULM' are each independently according to chemical structure:
wherein:
Optionally modifying any one or more of R 1'、R2' and R 3' of ULM-I to bind a linker group that is further covalently bonded to the PTM group when PTM is not ULM ', or optionally modifying one or more of R 1'、R2'、R3' of each of ULM and ULM ' to be covalently bonded to each other directly or through the linker group when PTM is ULM ', or
Pharmaceutically acceptable salts, enantiomers, diastereomers, solvates or polymorphs thereof.
In a further preferred aspect of the invention, R 1' of ULM-g to ULM-i is preferably hydroxy or a group metabolisable to hydroxy or carboxy, such that the compound represents a prodrug form of the active compound. Exemplary preferred R 1' groups include, for example, - (CH 2)nOH、(CH2)n-O-(C1-C6) alkyl groups, - (CH 2)nCOOH、-(CH2O)n H, optionally substituted- (CH 2)nOC(O)-(C1-C6 alkyl), or optionally substituted- (CH 2)nC(O)-O-(C1-C6 alkyl) wherein n is 0 or 1 when R 1' is or contains a carboxylic acid group, hydroxy or amine groups, hydroxy groups, carboxylic acid groups or amines (each of which may be optionally substituted) may be further chemically modified to provide covalent attachment to the PTM group (including ULM) and the linker group to which it is bonded;
When present, X and X' of ULM-g and ULM-h are preferably c= O, C =s, -S (O) groups or S (O) 2 groups, more preferably c=o groups;
R 2' of ULM-g to ULM-i is preferably optionally substituted-NR 1 -T-aryl, optionally substituted-NR 1 -T-heteroaryl or optionally substituted-NR 1 -T-heterocycle, wherein R 1 is H or CH 3, preferably H and T are optionally substituted- (CH 2)n -groups, wherein each of the methylene groups may optionally be substituted by one or two substituents, preferably selected from halogen, amino acid side chains as described elsewhere herein or C 1-C3 alkyl, preferably one or two methyl groups, which may be optionally substituted, and n is 0 to 6, often 0, 1, 2 or 3, preferably 0 or 1 alternatively T may also be a- (CH 2O)n -group, - (OCH 2)n -group, - (CH 2CH2O)n -group, - (OCH 2CH2)n -group), all of which are optionally substituted.
Preferred aryl groups for R 2' of ULM-g to ULM-i include optionally substituted phenyl or naphthyl, preferably phenyl, wherein the phenyl or naphthyl is optionally attached to PTM groups (including ULM 'groups) via: a linker group, halogen (preferably F or Cl), an amine, a mono-or dialkylamine (preferably dimethylamine), F, cl, OH, COOH, C 1-C6 alkyl, preferably CH 3、CF3、OMe、OCF3、NO2 or CN groups (each of which may be substituted in the ortho, meta and/or para positions of the benzene ring, preferably para), optionally substituted phenyl (the phenyl itself optionally being linked via a linker group to a PTM group (including the ULM' group)), and/or at least one of F, cl, OH, COOH, CH 3、CF3、OMe、OCF3、NO2 or CN groups (in the ortho, meta and/or para positions of the benzene ring, preferably para), optionally substituted naphthyl, optionally substituted heteroaryl, preferably optionally substituted isoxazole including methyl-substituted isoxazole, optionally substituted oxazole including methyl-substituted oxazole, optionally substituted thiazole including methyl-substituted thiazole, optionally substituted isothiazole including methyl-substituted isothiazole, optionally substituted pyrrole including methyl-substituted pyrrole, optionally substituted imidazole including methyl imidazole, optionally substituted or methoxybenzyl imidazole, optionally substituted oximidazole or methyloximidazole, optionally substituted oxadiazole including methyl-substituted triazole, optionally substituted pyridinyl includes halogen- (preferably F) or methyl-substituted pyridinyl or oxapyridinyl (wherein the pyridinyl group is linked to the phenyl group through oxygen), optionally substituted furans, optionally substituted benzofurans, optionally substituted dihydrobenzofurans, optionally substituted indoles, indolizines or azaindolizines (2, 3 or 4-azaindolizines), optionally substituted quinolines, optionally substituted groups according to the chemical structure:
wherein:
S c of ULM-g to ULM-i is CHR SS、NRURE or O;
R HET of ULM-g to ULM-i is H, CN, NO 2, halogen (preferably Cl or F), optionally substituted C 1-C6 alkyl (preferably substituted with one or two hydroxy groups or up to three halogen groups (e.g. CF 3), optionally substituted O (C 1-C6 alkyl) (preferably substituted with one or two hydroxy groups or up to three halogen groups), or optionally substituted alkynyl-C≡C-R a, wherein R a is H or C 1-C6 alkyl (preferably C 1-C3 alkyl);
R SS of ULM-g to ULM-i is H, CN, NO 2, halogen (preferably F or Cl), optionally substituted C 1-C6 alkyl (preferably substituted with one or two hydroxy groups or up to three halogen groups), optionally substituted O (C 1-C6 alkyl) (preferably substituted with one or two hydroxy groups or up to three halogen groups), or optionally substituted-C (O) (C 1-C6 alkyl) (preferably substituted with one or two hydroxy groups or up to three halogen groups);
R URE of ULM-g to ULM-i is H, C 1-C6 alkyl (preferably H or C 1-C3 alkyl) or-C (O) (C 1-C6 alkyl), each of which is optionally substituted by one or two hydroxy groups or up to three halogens, preferably fluoro groups, or optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocycle, preferably such as piperidine, morpholine, pyrrolidine, tetrahydrofuran;
R PRO of ULM-g to ULM-i is H, optionally substituted C 1-C6 alkyl or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocyclyl selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with C 1-C3 alkyl, preferably methyl or halogen groups, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;
r PRO1 and R PRO2 of ULM-g to ULM-i are each independently H, optionally substituted C 1-C3 alkyl or together form a keto group, and
Each n of ULM-g to ULM-i is independently 0, 1, 2,3,4,5 or 6 (preferably 0 or 1), or an optionally substituted heterocycle, preferably tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine or morpholine (when substituted, each of which is preferably substituted with methyl or halogen (F, br, cl), each of which may be optionally linked to a PTM group (including ULM' groups) via a linker group).
In certain preferred aspects of the present invention,ULM-g to ULM-i are
The group(s) is (are) a radical,
Wherein R PRO and n of ULM-g to ULM-i are the same as above.
Preferred heteroaryl groups for R 2' of ULM-g to ULM-i include optionally substituted quinolines (which may be attached to a pharmacophore or substituted on any carbon atom within the quinoline ring), optionally substituted indoles, optionally substituted indolizines, optionally substituted azaindolizines, optionally substituted benzofurans including optionally substituted benzofurans, optionally substituted isoxazoles, optionally substituted thiazoles, optionally substituted isothiazoles, optionally substituted thiophenes, optionally substituted pyridines (2-, 3-, or 4-pyridines), optionally substituted imidazoles, optionally substituted pyrroles, optionally substituted diazoles, optionally substituted triazoles, tetrazoles, optionally substituted oximidazole, or groups according to the following chemical structure:
wherein:
S c of ULM-g to ULM-i is CHR SS、NRURE or O;
R HET of ULM-g to ULM-i is H, CN, NO 2, halogen (preferably Cl or F), optionally substituted C 1-C6 alkyl (preferably substituted with one or two hydroxy groups or up to three halogen groups (e.g. CF 3), optionally substituted O (C 1-C6 alkyl) (preferably substituted with one or two hydroxy groups or up to three halogen groups), or optionally substituted alkynyl-C≡C-R a, wherein R a of ULM-g to ULM-i is H or C 1-C6 alkyl (preferably C 1-C3 alkyl);
R SS of ULM-g to ULM-i is H, CN, NO 2, halogen (preferably F or Cl), optionally substituted C 1-C6 alkyl (preferably substituted with one or two hydroxy groups or up to three halogen groups), optionally substituted O (C 1-C6 alkyl) (preferably substituted with one or two hydroxy groups or up to three halogen groups), or optionally substituted-C (O) (C 1-C6 alkyl) (preferably substituted with one or two hydroxy groups or up to three halogen groups);
R URE of ULM-g to ULM-i is H, C 1-C6 alkyl (preferably H or C 1-C3 alkyl) or-C (O) (C 1-C6 alkyl), each of which is optionally substituted by one or two hydroxy groups or up to three halogen groups, preferably fluoro groups, or optionally substituted heterocycles, for example piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted, and
Y C for ULM-g to ULM-i is N or C-R YC, where R YC is H, OH, CN, NO 2, halogen (preferably Cl or F), optionally substituted C 1-C6 alkyl (preferably substituted with one or two hydroxy groups or up to three halogen groups (e.g. CF 3)), optionally substituted O (C 1-C6 alkyl) (preferably substituted with one or two hydroxy groups or up to three halogen groups) or optionally substituted alkynyl-C.ident.C-R a, where R a is H or C 1-C6 alkyl (preferably C 1-C3 alkyl), each of which may be linked to PTM groups (including ULM' groups) optionally via a linker group.
For R 2' of ULM-g to ULM-i, preferred heterocyclyl groups include tetrahydrofuran, tetrahydrothiophene, tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, dioxane or thiane, each of which may be optionally substituted, or a group according to the chemical structure:
Preferably, the method comprises the steps of, The group(s) is (are) a radical,
Wherein:
R PRO of ULM-g to ULM-i is H, optionally substituted C 1-C6 alkyl or optionally substituted aryl, heteroaryl or heterocyclyl;
r PRO1 and R PRO2 of ULM-g to ULM-i are each independently H, optionally substituted C 1-C3 alkyl or together form a keto group, and
Each n in ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5 or 6 (often 0 or 1), each of which may be linked to a PTM group (including ULM' groups), optionally via a linker group.
The preferred R 2' substituent for ULM-g to ULM-i is also particularly (and not exclusively) the R 2' substituent found in the identified compounds disclosed herein (which include the specific compounds disclosed in the present specification and the attached figures). Each of these R 2' substituents may be used in combination with any number of R 3' substituents also disclosed herein.
R 3' of ULM-g to ULM-i is preferably optionally substituted-T-aryl, optionally substituted-T-heteroaryl, optionally substituted-T-heterocycle, optionally substituted-NR 1 -T-heteroaryl or optionally substituted-NR 1 -T-heterocycle, wherein R 1 is H or C 1-C3 alkyl, preferably H or CH 3, T is an optionally substituted- (CH 2)n -group), wherein each of the methylene groups may be optionally substituted with one or two substituents, preferably selected from halogen, C 1-C3 alkyl or a side chain of an amino acid as described elsewhere herein, preferably methyl, which may be optionally substituted; and n is 0 to 6, often 0, 1,2 or 3, preferably 0 or 1 alternatively, T may also be a- (CH 2O)n -group, - (OCH 2)n -group, - (CH 2CH2O)n -group, - (OCH 2CH2)n -group), each of which is optionally substituted.
Preferred aryl groups for R 3' for ULM-g to ULM-i include optionally substituted phenyl or naphthyl, preferably phenyl, wherein the phenyl or naphthyl is optionally linked to PTM groups (including ULM' groups) via a linker group and/or halogen (preferably F or Cl), amine, mono-or dialkylamine (preferably dimethylamine), amido (preferably- (CH 2)m-NR1C(O)R2 groups, wherein m, R 1 and R 2 are as defined above), halogen (often F or Cl), OH, CH 3、CF3、OMe、OCF3、NO2, CN or S (O) 2RS groups (R S is C 1-C6 alkyl, optionally substituted aryl, Heteroaryl or heterocyclyl or (CH 2)mNR1R2 group), each of which may be substituted in the ortho, meta and/or para, preferably para, positions of the benzene ring), or aryl (preferably phenyl), heteroaryl or heterocycle. preferably, the substituent phenyl is optionally substituted phenyl (i.e., the substituent phenyl itself is preferably substituted with at least one of the linker groups to which F, cl, OH, SH, COOH, CH 3、CF3、OMe、OCF3、NO2, CN or PTM groups (including ULM' groups) are attached, wherein the substitution occurs in the ortho, meta and/or para positions of the phenyl ring, preferably para), optionally substituted includes naphthyl as described above, optionally substituted heteroaryl (preferably optionally substituted isoxazole includes methyl substituted isoxazole, optionally substituted oxazole includes methyl substituted oxazole, optionally substituted thiazole includes methyl substituted thiazole, optionally substituted pyrrole includes methyl substituted pyrrole, optionally substituted imidazole includes methylimidazole, Benzyl imidazole or methoxybenzyl imidazole, oximidazole or methyloximidazole, optionally substituted diazolyl comprises methyl diazolyl, optionally substituted triazolyl comprises methyl substituted triazolyl, pyridyl comprises halogen- (preferably F) or methyl substituted pyridyl or oxapyridyl (wherein the pyridyl group is linked to the phenyl group by oxygen) or optionally substituted heterocycle (tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, morpholine, piperazine, tetrahydroquinoline, dioxane or thiane). Each of the aryl, heteroaryl, or heterocyclyl groups may be optionally linked to the PTM group (including the ULM' group) via a linker group.
Preferred heteroaryl groups for R 3' of ULM-g to ULM-i include optionally substituted quinolines (which may be attached to a pharmacophore or substituted on any carbon atom within the quinoline ring), optionally substituted indoles (including indolines), optionally substituted indolizines, optionally substituted azaindolizines (2, 3 or 4-azaindolizines), optionally substituted benzimidazoles, benzodiazoles, benzofurans, optionally substituted imidazoles, optionally substituted isoxazoles, optionally substituted oxazoles (preferably methyl substituted), optionally substituted diazoles, optionally substituted triazoles, tetrazoles, optionally substituted benzofurans, optionally substituted thiophenes, optionally substituted thiazoles (preferably methyl and/or thiol substituted), optionally substituted isothiazoles, optionally substituted triazoles (preferably methyl, triisopropylsilyl, optionally substituted (CH 2)m-O-C1-C6 alkyl or optionally substituted- (CH 2)m-C(O)-O-C1-C6 alkyl substituted 1,2, 3-triazoles), optionally substituted pyridines (2-, 3-or 4-pyridines) or groups according to the following chemical structure:
wherein:
S c of ULM-g to ULM-i is CHR SS、NRURE or O;
R HET of ULM-g to ULM-i is H, CN, NO 2, halogen (preferably Cl or F), optionally substituted C 1-C6 alkyl (preferably substituted with one or two hydroxy groups or up to three halogen groups (e.g. CF 3), optionally substituted O (C 1-C6 alkyl) (preferably substituted with one or two hydroxy groups or up to three halogen groups), or optionally substituted alkynyl-C≡C-R a, wherein R a is H or C 1-C6 alkyl (preferably C 1-C3 alkyl);
R SS of ULM-g to ULM-i is H, CN, NO 2, halogen (preferably F or Cl), optionally substituted C 1-C6 alkyl (preferably substituted with one or two hydroxy groups or up to three halogen groups), optionally substituted O (C 1-C6 alkyl) (preferably substituted with one or two hydroxy groups or up to three halogen groups), or optionally substituted-C (O) (C 1-C6 alkyl) (preferably substituted with one or two hydroxy groups or up to three halogen groups);
R URE of ULM-g to ULM-i is H, C 1-C6 alkyl (preferably H or C 1-C3 alkyl) or-C (O) (C 1-C6 alkyl), each of which is optionally substituted by one or two hydroxy groups or up to three halogen groups, preferably fluoro groups, or optionally substituted heterocycles, for example piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted, and
Y C for ULM-g to ULM-i is N or C-R YC, where R YC is H, OH, CN, NO 2, halogen (preferably Cl or F), optionally substituted C 1-C6 alkyl (preferably substituted by one or two hydroxy groups or up to three halogen groups (e.g. CF 3)), optionally substituted O (C 1-C6 alkyl) (preferably substituted by one or two hydroxy groups or up to three halogen groups) or optionally substituted alkynyl-C.ident.C-R a, where R a is H or C 1-C6 alkyl (preferably C 1-C3 alkyl). The heteroaryl groups may each be optionally linked to a PTM group (including ULM' groups) via a linker group.
For R 3' of ULM-g to ULM-i, preferred heterocyclyl groups include tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, tetrahydrofuran, tetrahydrothiophene, dioxane, and thiane, each of which may be optionally substituted, or a group according to the chemical structure:
preferably
The group(s) is (are) a radical,
Wherein:
R PRO of ULM-g to ULM-i is H, optionally substituted C 1-C6 alkyl or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocyclyl selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with C 1-C3 alkyl, preferably methyl or halogen groups, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;
r PRO1 and R PRO2 of ULM-g to ULM-i are each independently H, optionally substituted C 1-C3 alkyl or together form a keto group, and
Each n in ULM-g to ULM-i is 0,1, 2, 3, 4, 5 or 6 (preferably 0 or 1), wherein each of the heterocyclic groups may be linked to a PTM group (including ULM' groups), optionally via a linker group.
The preferred R 3' substituent for ULM-g to ULM-i is also particularly (and not exclusively) the R 3' substituent found in the identified compounds disclosed herein (which include the specific compounds disclosed in the present specification and the attached figures). Each of these R 3' substituents may be used in combination with any number of R 2' substituents also disclosed herein.
In certain alternative preferred embodiments, R 2' of ULM-g to ULM-i is an optionally substituted-NR 1-XR2' -alkyl group, -NR 1-XR2' -aryl group, an optionally substituted-NR 1-XR2' -HET, an optionally substituted-NR 1-XR2' -aryl-HET or an optionally substituted-NR 1-XR2' -HET-aryl,
Wherein:
R 1 of ULM-g to ULM-i is H or C 1-C3 alkyl (preferably H);
ULM-g to ULM-i X R2' is optionally substituted-CH 2)n-、–CH2)n-CH(Xv)＝CH(Xv) (cis or trans), -CH 2)n-CH≡CH-、-(CH2CH2O)n -or C 3-C6 cycloalkyl, and
X v of ULM-g to ULM-i is H, halogen or C 1-C3 alkyl optionally substituted with one or two hydroxy groups or up to three halogen groups;
The alkyl groups of ULM-g to ULM-i are optionally substituted C1-C 10 alkyl (preferably C 1-C6 alkyl) groups (in certain preferred embodiments, the alkyl groups are often terminated with halogen groups, either Cl or Br);
Aryl groups of ULM-g to ULM-i are optionally substituted phenyl or naphthyl (preferably phenyl), and
HET of ULM-g to ULM-i is optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, indolizine, azaindolizine, quinoline (each preferably substituted with a C 1-C3 alkyl group, preferably methyl or halogen groups, preferably F or Cl when substituted) or a group according to the chemical structure:
S c of ULM-g to ULM-i is CHR SS、NRURE or O;
R HET of ULM-g to ULM-i is H, CN, NO 2, halogen (preferably Cl or F), optionally substituted C 1-C6 alkyl (preferably substituted with one or two hydroxy groups or up to three halogen groups (e.g. CF 3), optionally substituted O (C 1-C6 alkyl) (preferably substituted with one or two hydroxy groups or up to three halogen groups), or optionally substituted alkynyl-C≡C-R a, wherein R a is H or C 1-C6 alkyl (preferably C 1-C3 alkyl);
R SS of ULM-g to ULM-i is H, CN, NO 2, halogen (preferably F or Cl), optionally substituted C 1-C6 alkyl (preferably substituted with one or two hydroxy groups or up to three halogen groups), optionally substituted O (C 1-C6 alkyl) (preferably substituted with one or two hydroxy groups or up to three halogen groups), or optionally substituted-C (O) (C 1-C6 alkyl) (preferably substituted with one or two hydroxy groups or up to three halogen groups);
R URE of ULM-g to ULM-i is H, C 1-C6 alkyl (preferably H or C 1-C3 alkyl) or-C (O) (C 1-C6 alkyl), each of which is optionally substituted by one or two hydroxy groups or up to three halogen groups, preferably fluoro groups, or optionally substituted heterocycles, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;
Y C of ULM-g to ULM-i is N or C-R YC, wherein R YC is H, OH, CN, NO 2, halogen (preferably Cl or F), optionally substituted C 1-C6 alkyl (preferably substituted with one or two hydroxy groups or up to three halogen groups (e.g. CF 3)), optionally substituted O (C 1-C6 alkyl) (preferably substituted with one or two hydroxy groups or up to three halogen groups) or optionally substituted alkynyl-c≡c-R a, wherein R a is H or C 1-C6 alkyl (preferably C 1-C3 alkyl);
R PRO of ULM-g to ULM-i is H, optionally substituted C 1-C6 alkyl or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocyclyl selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with C 1-C3 alkyl, preferably methyl or halogen groups, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;
r PRO1 and R PRO2 of ULM-g to ULM-i are each independently H, optionally substituted C 1-C3 alkyl or together form a keto group, and
Each n of ULM-g to ULM-i is independently 0,1, 2, 3, 4, 5 or 6 (preferably 0 or 1).
Each of the groups may optionally be linked to a PTM group (including ULM' groups) via a linker group.
In certain alternative preferred embodiments of the invention, R 3' of ULM-g to ULM-i is an optionally substituted- (CH 2)n-(V)n'-(CH2)n-(V)n'-RS3' group, an optionally substituted- (CH 2)n-N(R1')(C＝O)m'-(V)n'-RS3' group, an optionally substituted-X R3' -alkyl, an optionally substituted-X R3' -aryl group; an optionally substituted-X R3' -HET group, an optionally substituted-X R3' -aryl-HET group or an optionally substituted-X R3' -HET-aryl group,
Wherein:
R S3' is an optionally substituted alkyl (C 1-C10, preferably C 1-C6 alkyl), an optionally substituted aryl or HET group;
R 1' is H or C 1-C3 alkyl (preferably H);
V is O, S or NR 1';
X R3' is –(CH2)n-、-(CH2CH2O)n-、–CH2)n-CH(Xv)＝CH(Xv)-( cis or trans), -CH 2)n -CH≡CH-, or C 3-C6 cycloalkyl, all optionally substituted;
X V is H, halogen or C 1-C3 alkyl, optionally substituted with one or two hydroxy groups or up to three halogen groups;
Alkyl is an optionally substituted C 1-C10 alkyl (preferably C 1-C6 alkyl) group (in certain preferred embodiments, the alkyl is capped with a halogen group, often Cl or Br);
Aryl is optionally substituted phenyl or naphthyl (preferably phenyl), and
HET is optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, indolizine, azaindolizine, quinoline (each preferably substituted with a C 1-C3 alkyl group, preferably a methyl or halogen group, preferably F or Cl) or a group according to the chemical structure:
S c of ULM-g to ULM-i is CHR SS、NRURE or O;
R HET of ULM-g to ULM-i is H, CN, NO 2, halogen (preferably Cl or F), optionally substituted C 1-C6 alkyl (preferably substituted with one or two hydroxy groups or up to three halogen groups (e.g. CF 3), optionally substituted O (C 1-C6 alkyl) (preferably substituted with one or two hydroxy groups or up to three halogen groups), or optionally substituted alkynyl-C≡C-R a, wherein R a is H or C 1-C6 alkyl (preferably C 1-C3 alkyl);
R SS of ULM-g to ULM-i is H, CN, NO 2, halogen (preferably F or Cl), optionally substituted C 1-C6 alkyl (preferably substituted with one or two hydroxy groups or up to three halogen groups), optionally substituted O (C 1-C6 alkyl) (preferably substituted with one or two hydroxy groups or up to three halogen groups), or optionally substituted-C (O) (C 1-C6 alkyl) (preferably substituted with one or two hydroxy groups or up to three halogen groups);
R URE of ULM-g to ULM-i is H, C 1-C6 alkyl (preferably H or C 1-C3 alkyl) or-C (O) (C 0-C6 alkyl), each of which is optionally substituted by one or two hydroxy groups or up to three halogen groups, preferably fluoro groups, or optionally substituted heterocycles, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;
Y C of ULM-g to ULM-i is N or C-R YC, wherein R YC is H, OH, CN, NO 2, halogen (preferably Cl or F), optionally substituted C 1-C6 alkyl (preferably substituted with one or two hydroxy groups or up to three halogen groups (e.g. CF 3)), optionally substituted O (C 1-C6 alkyl) (preferably substituted with one or two hydroxy groups or up to three halogen groups) or optionally substituted alkynyl-c≡c-R a, wherein R a is H or C 1-C6 alkyl (preferably C 1-C3 alkyl);
R PRO of ULM-g to ULM-i is H, optionally substituted C 1-C6 alkyl or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocyclyl selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with C 1-C3 alkyl, preferably methyl or halogen groups, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;
R PRO1 and R PRO2 of ULM-g to ULM-i are each independently H, optionally substituted C 1-C3 alkyl or together form a keto group;
each n of ULM-g to ULM-i is independently 0,1, 2, 3, 4, 5 or 6 (preferably 0 or 1);
each m' of ULM-g to ULM-i is 0 or 1, and
Each n' of ULM-g to ULM-i is 0 or 1;
Wherein each of said compounds is preferably attached to a PTM group (including ULM' groups) on an alkyl, aryl or Het group, optionally via a linker group.
In alternative embodiments, R 3' of ULM-g to ULM-i is- (CH 2)n -aryl, - (CH 2CH2O)n -aryl, - (CH 2)n -HET or- (CH 2CH2O)n -HET),
Wherein:
Said aryl of ULM-g to ULM-i is phenyl optionally substituted with one or two substituents, wherein said substituents are preferably selected from- (CH 2)n OH, C 1-C6 alkyl which is itself further optionally substituted with CN, halogen (up to three halogen groups), OH, - (CH 2)nO(C1-C6) alkyl, amine, mono-or di- (C 1-C6 alkyl) amine, wherein alkyl on said amine is optionally substituted with 1 or 2 hydroxy or up to three halogen (preferably F, cl) groups, or
Said aryl groups of ULM-g to ULM-i are substituted as follows: - (CH 2)nOH、-(CH2)n-O-(C1-C6) alkyl, - (CH 2)n-O-(CH2)n-(C1-C6) alkyl, - (CH 2)n-C(O)(C0-C6) alkyl, - (CH 2)n-C(O)O(C0-C6) alkyl, - (CH 2)n-OC(O)(C0-C6) alkyl, amine, mono-or di- (C 1-C6 alkyl) amine (wherein the alkyl on the amine is optionally substituted by 1 or 2 hydroxy groups or up to three halo (preferably F, cl) groups) CN, NO 2, optionally substituted- (CH 2)n-(V)m'-CH2)n-(V)m'-(C1-C6) alkyl, - (V) m'-(CH2CH2O)n-RPEG groups, wherein V is O, S or NR 1',R1' is H or C 1-C3 alkyl (preferably H), and R PEG is H or optionally substituted (including optionally substituted by carboxy) C 1-C6 alkyl, or
Said aryl group of ULM-g to ULM-i is optionally substituted with a heterocycle comprising heteroaryl selected from oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, quinoline, benzofuran, indole, indolizine, azaindolizine (each preferably substituted with C 1-C3 alkyl when substituted, preferably methyl or halogen groups, preferably F or Cl), or groups according to the chemical structure:
S c of ULM-g to ULM-i is CHR SS、NRURE or O;
R HET of ULM-g to ULM-i is H, CN, NO 2, halogen (preferably Cl or F), optionally substituted C 1-C6 alkyl (preferably substituted with one or two hydroxy groups or up to three halogen groups (e.g. CF 3), optionally substituted O (C 1-C6 alkyl) (preferably substituted with one or two hydroxy groups or up to three halogen groups), or optionally substituted alkynyl-C≡C-R a, wherein R a is H or C 1-C6 alkyl (preferably C 1-C3 alkyl);
R SS of ULM-g to ULM-i is H, CN, NO 2, halogen (preferably F or Cl), optionally substituted C 1-C6 alkyl (preferably substituted with one or two hydroxy groups or up to three halogen groups), optionally substituted O (C 1-C6 alkyl) (preferably substituted with one or two hydroxy groups or up to three halogen groups), or optionally substituted-C (O) (C 1-C6 alkyl) (preferably substituted with one or two hydroxy groups or up to three halogen groups);
R URE of ULM-g to ULM-i is H, C 1-C6 alkyl (preferably H or C 1-C3 alkyl) or-C (O) (C 0-C6 alkyl), each of which is optionally substituted by one or two hydroxy groups or up to three halogen groups, preferably fluoro groups, or optionally substituted heterocycles, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;
Y C of ULM-g to ULM-i is N or C-R YC, wherein R YC is H, OH, CN, NO 2, halogen (preferably Cl or F), optionally substituted C 1-C6 alkyl (preferably substituted with one or two hydroxy groups or up to three halogen groups (e.g. CF 3)), optionally substituted O (C 1-C6 alkyl) (preferably substituted with one or two hydroxy groups or up to three halogen groups) or optionally substituted alkynyl-c≡c-R a, wherein R a is H or C 1-C6 alkyl (preferably C 1-C3 alkyl);
R PRO of ULM-g to ULM-i is H, optionally substituted C 1-C6 alkyl or optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocyclyl selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with C 1-C3 alkyl, preferably methyl or halogen groups, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;
R PRO1 and R PRO2 of ULM-g to ULM-i are each independently H, optionally substituted C 1-C3 alkyl or together form a keto group;
HET of ULM-g to ULM-i is preferably an oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C 1-C3 alkyl group, preferably a methyl or halogen group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine, or a group according to the chemical structure:
S c of ULM-g to ULM-i is CHR SS、NRURE or O;
R HET of ULM-g to ULM-i is H, CN, NO 2, halogen (preferably Cl or F), optionally substituted C 1-C6 alkyl (preferably substituted with one or two hydroxy groups or up to three halogen groups (e.g. CF 3), optionally substituted O (C 1-C6 alkyl) (preferably substituted with one or two hydroxy groups or up to three halogen groups), or optionally substituted alkynyl-C≡C-R a, wherein R a is H or C 1-C6 alkyl (preferably C 1-C3 alkyl);
R SS of ULM-g to ULM-i is H, CN, NO 2, halogen (preferably F or Cl), optionally substituted C 1-C6 alkyl (preferably substituted with one or two hydroxy groups or up to three halogen groups), optionally substituted O (C 1-C6 alkyl) (preferably substituted with one or two hydroxy groups or up to three halogen groups), or optionally substituted-C (O) (C 1-C6 alkyl) (preferably substituted with one or two hydroxy groups or up to three halogen groups);
R URE of ULM-g to ULM-i is H, C 1-C6 alkyl (preferably H or C 1-C3 alkyl) or-C (O) (C 0-C6 alkyl), each of which is optionally substituted by one or two hydroxy groups or up to three halogen groups, preferably fluoro groups, or optionally substituted heterocycles, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;
Y C of ULM-g to ULM-i is N or C-R YC, wherein R YC is H, OH, CN, NO 2, halogen (preferably Cl or F), optionally substituted C 1-C6 alkyl (preferably substituted with one or two hydroxy groups or up to three halogen groups (e.g. CF 3)), optionally substituted O (C 1-C6 alkyl) (preferably substituted with one or two hydroxy groups or up to three halogen groups) or optionally substituted alkynyl-c≡c-R a, wherein R a is H or C 1-C6 alkyl (preferably C 1-C3 alkyl);
R PRO of ULM-g to ULM-i is H, optionally substituted C 1-C6 alkyl or optionally substituted aryl, heteroaryl or heterocyclyl;
R PRO1 and R PRO2 of ULM-g to ULM-i are each independently H, optionally substituted C 1-C3 alkyl or together form a keto group;
each m' of ULM-g to ULM-i is independently 0 or 1, and
Each n of ULM-g to ULM-i is independently 0,1, 2, 3, 4, 5 or 6 (preferably 0 or 1),
Wherein each of said compounds is preferably linked to a PTM group (including ULM' groups) on said alkyl or Het groups, optionally via a linker group.
In yet other embodiments, preferred compounds include compounds according to the following chemical structure:
wherein:
r 1' of ULM-i is OH or a group that is metabolized or subjected to OH in the patient;
r 2' of ULM-i is-NH-CH 2 -aryl-HET (preferably phenyl directly attached to methyl substituted thiazole);
R 3' of ULM-i is a-CHR CR3'-NH-C(O)-R3P1 group or a-CHR CR3'-R3P2 group;
R CR3' of ULM-i is C 1-C4 alkyl, preferably methyl, isopropyl or tert-butyl;
R 3P1 of ULM-i is C 1-C3 alkyl (preferably methyl), an optionally substituted oxetanyl group (preferably methyl substituted, - (CH 2)nOCH3 group wherein n is 1 or 2 (preferably 2), or A group (ethyl ether group is preferably substituted on the phenyl moiety), morpholino group (attached to the carbonyl group at the 2-or 3-position;
R 3P2 of ULM-i is A group;
aryl of ULM-i is phenyl;
HET of ULM-i is optionally substituted thiazole or isothiazole, and
R HET of ULM-i is H or a halogen group (preferably H);
or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof, wherein each of said compounds is optionally linked to a PTM group (including ULM' groups) via a linker group.
In certain aspects, the bifunctional compound comprises a ubiquitin E3 ligase binding moiety (ULM), wherein ULM is a group according to the following chemical structure:
wherein:
Each R 5 and R 6 of ULM-j is independently OH, SH or optionally substituted alkyl or R 5、R6, and the carbon atom to which they are attached forms a carbonyl group;
R 7 of ULM-j is H or optionally substituted alkyl;
e of ULM-j is a bond, c=o or c=s;
g of ULM-J is a bond, optionally substituted alkyl, -COOH or c=j;
j of ULM-J is O or N-R 8;
R 8 of ULM-j is H, CN, optionally substituted alkyl or optionally substituted alkoxy;
M of ULM-j is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl or
Each R 9 and R 10 of ULM-j is independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl, disulfide-linked ULM, optionally substituted heteroaryl or haloalkyl, or R 9、R10 and the carbon atom to which they are attached form optionally substituted cycloalkyl;
R 11 of ULM-j is optionally substituted heterocycle, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl or
R 12 of ULM-j is H or optionally substituted alkyl;
r 13 of ULM-j is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl) alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl) carbonyl or optionally substituted aralkyl, optionally substituted (oxo-alkyl) carbamate,
Each R 14 of ULM-j is independently H, haloalkyl, optionally substituted cycloalkyl, optionally substituted alkyl, or optionally substituted heterocycloalkyl;
R 15 of ULM-j is H, optionally substituted heteroaryl, haloalkyl, optionally substituted aryl, optionally substituted alkoxy or optionally substituted heterocyclyl;
Each R 16 of ULM-j is independently halogen, optionally substituted alkyl, optionally substituted haloalkyl, CN, or optionally substituted haloalkoxy;
Each R 25 of ULM-j is independently H or optionally substituted alkyl, or two R 25 groups may together form oxo or optionally substituted cycloalkyl;
R 23 of ULM-j is H or OH;
z 1、Z2、Z3 and Z 4 of ULM-j are independently C or N, and
O of ULM-j is 0, 1,2,3 or 4, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.
In certain embodiments, wherein G of ULM-J is c=j, J is O, R 7 is H, each R 14 is H, and O is 0.
In certain embodiments, wherein G of ULM-J is c=j, J is O, R 7 is H, each R 14 is H, R 15 is optionally substituted heteroaryl, and O is 0. In other cases, E is c=o and M is
In certain embodiments, wherein E of ULM-j is c=o, R 11 is an optionally substituted heterocycle orAnd M is
In certain embodiments, wherein E of ULM-j is c=o and M isAnd R 11 isEach R 18 is independently halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl or haloalkoxy, and p is 0,1, 2,3 or 4.
In certain embodiments, the ULM and the present ULM' are each independently a group according to the chemical structure:
wherein:
g of ULM-k is c=j, J is O;
r 7 of ULM-k is H;
Each R 14 of ULM-k is H;
o of ULM-k is 0;
R 15 of ULM-k is And
R 17 of ULM-k is H, halogen, optionally substituted cycloalkyl, optionally substituted alkyl, optionally substituted alkenyl and haloalkyl.
In other cases, R 17 of ULM-k is alkyl (e.g., methyl) or cycloalkyl (e.g., cyclopropyl).
In other embodiments, the ULM and the present ULM' are each independently a group according to the chemical structure:
wherein:
g of ULM-k is c=j, J is O;
r 7 of ULM-k is H;
Each R 14 of ULM-k is H;
O of ULM-k is 0, and
R 15 of ULM-k is selected from:
Wherein R 30 of ULM-k is H or optionally substituted alkyl.
In other embodiments, the ULM and the present ULM' are each independently a group according to the chemical structure:
wherein:
e of ULM-k is c=o;
m of ULM-k is And
R 11 of ULM-k is selected from:
In still other embodiments, the chemical structure of the compound,
Wherein:
e of ULM-k is c=o;
r 11 of ULM-k is And
M of ULM-k is
Q of ULM-k is 1 or 2;
R 20 of ULM-k is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, Or;
R 21 of ULM-k is H or optionally substituted alkyl, and
R 22 of ULM-k is H, optionally substituted alkyl, optionally substituted alkoxy or haloalkyl.
In any of the embodiments described herein, R 11 of ULM-j or ULM-k is selected from:
In certain embodiments, R 11 of ULM-j or ULM-k is selected from:
in certain embodiments, the ULM (or the ULM's present) are groups according to the following chemical structure:
wherein:
x of ULM-l is O or S;
y of ULM-l is H, methyl or ethyl;
R 17 of ULM-l is H, methyl, ethyl, hydroxymethyl or cyclopropyl;
m of ULM-l is optionally substituted aryl, optionally substituted heteroaryl or
R 9 of ULM-l is H;
R 10 of ULM-l is H, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl or cycloalkyl;
R11 of ULM-l is optionally substituted heteroaromatic, optionally substituted heterocycle, optionally substituted aryl or
R 12 of ULM-l is H or optionally substituted alkyl, and
R 13 of ULM-l is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl) alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl) carbonyl or optionally substituted aralkyl, optionally substituted (oxo alkyl) carbamate.
In some embodiments, the ULM and the present ULM' are each independently a group according to the chemical structure:
wherein:
Y of ULM-m is H, methyl or ethyl;
r 9 of ULM-m is H;
R 10 is isopropyl, tert-butyl, sec-butyl, cyclopentyl or cyclohexyl;
R 11 of ULM-m is optionally substituted amide, optionally substituted isoindolinone, optionally substituted isoxazole, optionally substituted heterocycle.
In other preferred embodiments of the invention, the ULM and the present ULM' are each independently a group according to the following chemical structure:
wherein:
R 17 of ULM-n is methyl, ethyl or cyclopropyl, and
R 9、R10 and R 11 of ULM-n are as defined above. In other cases, R 9 is H, and
R 10 of ULM-n is H, alkyl or cycloalkyl (preferably isopropyl, tert-butyl, sec-butyl, cyclopentyl or cyclohexyl).
In any aspect or embodiment described herein, a ULM (or an existing ULM') as described herein may be a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, or polymorph thereof. In addition, in any aspect or embodiment described herein, a ULM (or an existing ULM') as described herein may be directly coupled to a PTM via a bond or chemical linker.
In certain aspects of the invention, the ULM moiety is selected from:
Wherein the VLM may be attached to the PTM at any suitable position via a linker as described herein, including for example aryl, heteroaryl, phenyl or phenyl of an indole group, optionally via any suitable functional group, such as an amine, ester, ether, alkyl or alkoxy group.
Exemplary CLM:
in any aspect or embodiment described herein, the instructions provide compounds useful for binding and/or inhibiting cereblon (e.g., ULM is CLM, PTM is CLM, or both ULM and PTM are CLM).
In some embodiments, the ULM is CLM, which is thalidomide, lenalidomide, pomalidomide, analogs thereof, isosteres thereof, or derivatives thereof.
Novel imide compounds
In certain embodiments, CLM is selected from the following chemical structures:
wherein:
W is selected from CH 2、CHR、C＝O、SO2, NH, and N-alkyl;
each X is independently selected from O, S and H 2;
Y is selected from CH 2, -C=CR', NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O, and S;
z is selected from O, S and H 2;
g and G 'are independently selected from H, alkyl (straight chain, branched, optionally substituted with R'), OH, R 'OCOOR, R' OCONRR, CH 2 -heterocyclyl optionally substituted with R ', and benzyl optionally substituted with R';
Q 1、Q2、Q3 and Q 4 represent carbon C substituted with a group independently selected from R', N or N-oxide;
a is independently selected from H, alkyl, cycloalkyl, cl and F;
R includes, but is not limited to, -CONR ' R ', -OR ', -NR ' R ', -SR ', -SO 2R'、-SO2 NR ' R ', -CR ' R ' -, -CR ' NR ' R ' -, -aryl, -heteroaryl, -alkyl (straight, branched, optionally substituted), -cycloalkyl, -heterocyclyl 、-P(O)(OR')R"、-P(O)R'R"、-OP(O)(OR')R"、-OP(O)R'R"、-Cl、-F、-Br、-I、-CF3、-CN、-NR'SO2NR'R"、-NR'CONR'R",-CONR'COR"、NR'C(＝N-CN)NR'R"、-C(＝N-CN)NR'R"、-NR'C(＝N-CN)R"、-NR'C(＝C-NO2)NR'R"、-SO2NR'COR"、-NO2、-CO2R'、-C(C＝N-OR')R"、-CR'＝CR'R"、-CCR'、-S(C＝O)(C＝N-R')R"、-SF5, OR-OCF 3;
r' and R "are independently selected from a bond, H, N, N-oxide, alkyl (straight, branched), cycloalkyl, aryl, heteroaryl, heterocycle, -C (=o) R, or heterocyclyl, each of which is optionally substituted;
represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific, and
R n contains a functional group or atom,
Wherein n is an integer from 1 to 4, and wherein:
When n is 1, R n is modified to be covalently linked to the linker group (L), and
When n is 2,3 or 4, then one R n is modified to covalently attach to the linker group (L), and optionally any other R n is modified to covalently attach to PTM, CLM, a second CLM having the same chemical structure as CLM, CLM', a second linker, or any multiple or combination thereof.
Exemplary CLM
In any of the compounds described herein, CLM comprises a chemical structure selected from the group consisting of:
wherein:
w is independently selected from CH 2、CHR、C＝O、SO2, NH, and N-alkyl;
x is independently selected from O, S and H 2;
Y is independently selected from CH 2, -C=CR', NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O, and S;
z is independently selected from O, S or H 2, except that neither X nor Z is H2;
g and G 'are independently selected from H, alkyl (straight chain, branched, optionally substituted with R'), OH, R 'OCOOR, R' OCONRR, CH 2 -heterocyclyl optionally substituted with R ', and benzyl optionally substituted with R';
Q1-Q4 represent carbon C substituted with groups independently selected from R', N or N-oxides;
a is independently selected from H, alkyl, cycloalkyl, cl and F;
R includes, but is not limited to, -CONR ' R ', -OR ', -NR ' R ', -SR ', -SO 2R'、-SO2 NR ' R ', -CR ' R ' -, -CR ' NR ' R ' -, -aryl, -heteroaryl, -alkyl (straight, branched, optionally substituted), -cycloalkyl, -heterocyclyl 、-P(O)(OR')R"、-P(O)R'R"、-OP(O)(OR')R"、-OP(O)R'R"、-Cl、-F、-Br、-I、-CF3、-CN、-NR'SO2NR'R"、-NR'CONR'R",-CONR'COR"、NR'C(＝N-CN)NR'R"、-C(＝N-CN)NR'R"、-NR'C(＝N-CN)R"、-NR'C(＝C-NO2)NR'R"、SO2NR'COR"、-NO2、-CO2R'、-C(C＝N-OR')R"、-CR'＝CR'R"、-CCR'、-S(C＝O)(C＝N-R')R"、-SF5, OR-OCF 3;
r' and R "are independently selected from a bond, H, N, N-oxide, alkyl (straight, branched), cycloalkyl, aryl, heteroaryl, heterocycle, -C (=o) R, or heterocyclyl, each of which is optionally substituted;
n is an integer from 1 to 4;
represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific, and
Rn comprises 1-4 independent functional groups or atoms, and optionally one of them is modified to be covalently linked to ABM, chemical linker group (L), ULM, CLM (or CLM'), or a combination thereof.
In certain embodiments described herein, the CLM or ULM comprises a chemical structure selected from the group consisting of:
wherein:
W is independently selected from CH 2, c= O, NH, and N-alkyl;
r is independently selected from H, methyl, alkyl;
represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific, and
Rn comprises 1-4 independently selected functional groups or atoms, and optionally one of them is modified to be covalently linked to a PTM, chemical linker group (L), CLM (or CLM'), or a combination thereof.
In some embodiments, the CLM is represented by the following structure, wherein the dashed lines indicate the joint attachment points:
More specifically, non-limiting examples of CLMs include those shown below as well as those "hybrid" molecules that result from a combination of 1 or more different features shown in the molecules below.
In any of the compounds described herein, CLM comprises a chemical structure selected from the group consisting of:
wherein:
W of formulas (h) through (ab) are independently selected from CH 2、CHR、C＝O、SO2, NH, and N-alkyl;
q 1、Q2、Q3、Q4、Q5 of formulas (h) to (ab) independently represents carbon C substituted with a group independently selected from R', N or N-oxide;
r 1 of formulas (H) to (ab) is selected from H, CN, C1-C3 alkyl;
r 2 of formulas (H) to (ab) is selected from H, CN, C1-C3 alkyl, CHF 2、CF3, CHO;
R 3 of formulas (H) to (ab) is selected from H, alkyl, substituted alkyl, alkoxy, substituted alkoxy;
R 4 of formulas (H) to (ab) is selected from H, alkyl, substituted alkyl;
R 5 of formulas (H) to (ab) is H or lower alkyl;
x of formulae (h) to (ab) is C, CH or N;
R' of formulas (H) to (ab) is selected from H, halogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy;
r of formulas (h) to (ab) is H, OH, lower alkyl, lower alkoxy, cyano, halogenated lower alkoxy or halogenated lower alkyl;
Of the formulae (h) to (ab) being a single bond or a double bond, and
CLM is covalently linked to PTM, a chemical linker group (L), ULM, CLM (or CLM'), or a combination thereof.
In any aspect or embodiment described herein, CLM or CLM ' is covalently linked to PTM, a chemical linker group (L), ULM, CLM, CLM ', or a combination thereof via an R group (e.g., R, R 1、R2、R3、R4 or R '), W, X, or Q group (e.g., Q 1、Q2、Q3、Q4 or Q 5) of formulas (h) to (ab).
In any of the embodiments described herein, CLM or CLM 'is covalently linked to PTM, chemical linker group (L), ULM, CLM, CLM', or a combination thereof via W、X、R、R1、R2、R3、R4、R5、R'、Q1、Q2、Q3、Q4 and Q 5 of formulas (h) to (ab).
In any of the embodiments described herein, W, X, R 1、R2、R3、R4、R'、Q1、Q2、Q3、Q4 and Q 5 of formulas (h) to (ab) can be independently covalently coupled to a linker and/or a linker attached to one or more PTM, ULM, ULM ', CLM or CLM' groups.
More specifically, non-limiting examples of CLMs include those shown below as well as "hybrid" molecules or compounds that result from combining 1 or more different characteristics of the following compounds:
wherein:
W of formulas (ac) through (an) is independently selected from CH 2、CHR、C＝O、SO2, NH, and N-alkyl;
R 1 of formulas (ac) to (an) is selected from H, CN, C1-C3 alkyl;
R 3 of formulas (ac) to (an) is selected from H, alkyl, substituted alkyl, alkoxy, substituted alkoxy;
r of formulae (ac) to (an) is H;
Is a single bond or a double bond, and
Rn of formulas (ac) through (an) contain a functional group or atom.
In any of the embodiments described herein, W, R 1、R2、Q1、Q2、Q3、Q4 and Rn of formulas (ac) to (an) may be independently covalently coupled to a linker and/or a linker attached to one or more PTM, ULM, ULM ', CLM or CLM' groups.
In any of the embodiments described herein, R 1、R2、Q1、Q2、Q3、Q4 and Rn of formulas (ac) to (an) may be independently covalently coupled to a linker and/or a linker attached to one or more PTM, ULM, ULM ', CLM or CLM' groups.
In any of the embodiments described herein, Q 1、Q2、Q3、Q4 and Rn of formulas (ac) to (an) may be independently covalently coupled to a linker and/or a linker attached to one or more PTM, ULM, ULM ', CLM or CLM' groups.
In any aspect or embodiment described herein, R n of formulas (ac) to (an) is modified to covalently attach to a linker group (L), PTM, ULM, a second CLM having the same chemical structure as CLM, CLM', a second linker, or any plurality or combination thereof.
In any aspect or embodiment described herein, the CLM is selected from the group consisting of:
Wherein R' is halogen and R 1 is as described above with respect to formulae (h) to (ab) or (ac) to (a).
In some cases, the CLM may be an imide that binds to the cereblon E3 ligase. These imide and linker attachment points may be, but are not limited to, the following structures:
wherein R' is halogen.
Exemplary joints:
in any aspect or embodiment comprising structure ULM-L-PTM, linker (L) comprises a chemical structural unit represented by the formula:
-(A)q-,
wherein:
a is a group attached to the ULM or PTM moiety, and
Q is an integer greater than or equal to 1,
Wherein A is selected from C 3-11 cycloalkyl optionally substituted with 0-6R L1 and/or R L2 groups, C 3-11 heterocyclyl optionally substituted with 0-6R L1 and/or R L2 groups, aryl optionally substituted with 0-6R L1 and/or R L2 groups, heteroaryl optionally substituted with 0-6R L1 and/or R L2 groups, wherein R L1 or R L2 are each independently optionally linked to other groups to form cycloalkyl and/or heterocyclyl moieties optionally substituted with 0-4R L5 groups;
R L1、RL2、RL3、RL4 and R L5 are each independently H, halogen, C 1-8 alkyl, OC 1-8 alkyl, SC 1-8 alkyl, NHC 1-8 alkyl, N (C 1-8 alkyl) 2、C3-11 cycloalkyl, aryl, heteroaryl, C 3-11 heterocyclyl, OC 1-8 cycloalkyl, SC 1-8 cycloalkyl, NHC 1-8 cycloalkyl, N (C 1-8 cycloalkyl) 2、N(C1-8 cycloalkyl) (C 1-8 alkyl), OH, NH 2、SH、SO2C1-8 alkyl, P (O) (OC 1-8 alkyl) (C 1-8 alkyl), P (O) (OC 1-8 alkyl) 2、CC-C1-8 alkyl, CCH, ch=ch (C 1-8 alkyl), C (C 1-8 alkyl) =ch (C 1-8 alkyl), c (C 1-8 alkyl) =c (C 1-8 alkyl) 2、Si(OH)3、Si(C1-8 alkyl) 3、Si(OH)(C1-8 alkyl) 2、COC1-8 alkyl, CO 2 H, halogen, CN, CF 3、CHF2、CH2F、NO2、SF5、SO2NHC1-8 alkyl, SO 2N(C1-8 alkyl) 2、SONHC1-8 alkyl, SON (C 1-8 alkyl) 2、CONHC1-8 alkyl, CON (C 1-8 alkyl) 2、N(C1-8 alkyl) CONH (C 1-8 alkyl), N (C 1-8 alkyl) CON (C 1-8 alkyl) 2、NHCONH(C1-8 alkyl), NHCON (C 1-8 alkyl) 2、NHCONH2、N(C1-8 alkyl) SO 2NH(C1-8 alkyl), N (C 1-8 alkyl) SO 2N(C1-8 alkyl) 2、NH SO2NH(C1-8 alkyl, NH SO 2N(C1-8 alkyl) 2、NH SO2NH2.
In any aspect or embodiment described herein, the linker (L) comprises the following chemical structure:
wherein:
W L1 and W L2 are each independently a 4-8 membered ring having 0-4 heteroatoms, optionally substituted with RQ, each RQ is independently H, halogen, OH, CN, CF3, C1-C6 alkyl (straight, branched, optionally substituted), C1-C6 alkoxy (straight, branched, optionally substituted), or 2 RQ groups together with the atoms to which they are attached form a 4-8 membered ring system containing 0-4 heteroatoms;
Y L1 is each independently a bond, C1-C6 alkyl (straight, branched, optionally substituted) and optionally one or more C atoms are replaced by O, or C1-C6 alkoxy (straight, branched, optionally substituted), and
The dashed lines indicate the attachment points to the PTM or ULM portions.
In any aspect or embodiment described herein, the linker (L) comprises the following chemical structure:
wherein:
W L1 and W L2 are each independently aryl, heteroaryl, cyclyl, heterocyclyl, C 1-6 alkyl, bicyclo, biaryl, or biaheterocyclyl, each optionally substituted with R Q, each R Q is independently H, halogen, OH, CN, CF 3, hydroxy, nitro, C≡CH, C 2-6 alkenyl, C 2-6 alkynyl, C 1-C6 alkyl (straight, branched, optionally substituted), C 1-C6 alkoxy (straight, branched, optionally substituted), OC 1-3 alkyl (optionally substituted with 1 or more-F), OH, NH 2、NRY1RY2, CN, or 2R Q groups together with the atoms to which they are attached form a 4-8 membered ring system containing 0-4 heteroatoms;
Y L1 are each independently a bond, NR YL1、O、S、NRYL2、CRYL1RYL2、C＝O、C＝S、SO、SO2、C1-C6 alkyl (linear, branched, optionally substituted), and optionally one or more C atoms replaced by O;
Q L is a 3-6 membered cycloaliphatic or aromatic ring having 0-4 heteroatoms, optionally bridged, optionally substituted with 0-6R Q, each R Q is independently H, C 1-6 alkyl (straight chain, branched, optionally substituted with 1 or more halogens, C 1-6 alkoxy), or 2R Q groups together with the atoms to which they are attached form a 3-8 membered ring system containing 0-2 heteroatoms);
R YL1、RYL2 is each independently H, OH, C 1-6 alkyl (straight chain, branched, optionally substituted with 1 or more halogens, C 1-6 alkoxy), or R 1、R2, together with the atoms to which they are attached, forms a 3-8 membered ring system containing 0-2 heteroatoms;
n is 0 to 10, and
The dashed lines indicate the attachment points to the PTM or ULM portions.
In some embodiments, the linker group (L) comprises a group represented by a general structure selected from the group consisting of:
-N(R)-(CH2)m-O(CH2)n-O(CH2)o-O(CH2)p-O(CH2)q-O(CH2)r-OCH2-,
-O-(CH2)m-O(CH2)n-O(CH2)o-O(CH2)p-O(CH2)q-O(CH2)r-OCH2-,
-O-(CH2)m-O(CH2)n-O(CH2)o-O(CH2)p-O(CH2)q-O(CH2)r-O-;
-N(R)-(CH2)m-O(CH2)n-O(CH2)o-O(CH2)p-O(CH2)q-O(CH2)r-O-;
-(CH2)m-O(CH2)n-O(CH2)o-O(CH2)p-O(CH2)q-O(CH2)r-O-;
-(CH2)m-O(CH2)n-O(CH2)o-O(CH2)p-O(CH2)q-O(CH2)r-OCH2-;
Wherein each m, N, O, p, q and R is independently 0, 1, 2, 3, 4, 5, 6, provided that when the number is zero, no N-O or O-O bond is present, R is selected from H, methyl or ethyl, and X is selected from H or F;
in some further embodiments, the linker (L) is selected from:
in some preferred embodiments, the linker (L) is selected from:
Wherein each n and m is independently 0, 1, 2, 3, 4, 5 or 6.
In some embodiments, L is an optionally substituted polyethyleneoxy group comprising 1 to 10 units.
In some further embodiments, L is a polyethylene group comprising 1 to 10 ethylene glycol units optionally substituted with aryl or phenyl.
In any embodiment, the compound comprises a plurality of ULMs, a plurality of PTMs, a plurality of linkers, or any combination thereof.
Exemplary Tau-PROTAC Compounds
As described above, in certain aspects, the present description provides difunctional PROTAC compounds comprising at least one PTM group, a linker, and at least one ULM (VLM or CLM) group as described herein.
In certain embodiments, the compound is selected from compounds 1-330 (e.g., selected from tables 1 or 2), and salts and polymorphs thereof.
In certain embodiments, the compound is selected from table 1 or 2 (i.e., the compound is selected from compounds 1-330), and salts and polymorphs thereof.
In any aspect or embodiment described herein, the compound is selected from formulas CI to CV:
wherein:
R 101 is 1-2 substituents independently selected from H, alkyl, halo, haloalkyl or cyano;
R 102 is selected from H, alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl;
r 103 is 1-2 substituents independently selected from H, alkyl, halo, haloalkyl or cyano;
R 104 is 1-2 substituents independently selected from H, alkyl, halo, haloalkyl or cyano;
r 105 is 1-2 substituents independently selected from H, alkyl, halo, haloalkyl or cyano;
R106、R107、R109、R110、R111、R112、R113、R114、R116、R117、R120、R121、R126、R127、R122 And R 123 are each independently selected from H, alkyl, halo, or haloalkyl;
R 108 is 1-2 substituents independently selected from H, alkyl, halo, haloalkyl, cyano or methoxy;
r 115 is selected from H, alkyl, and haloalkyl;
r 118 and R 119 are independently selected from H, alkyl, halogen or haloalkyl, or R 118 and R 119 together with the carbon atom to which they are attached represent a 3-6 membered cycloalkyl or heterocycloalkyl ring, for example cyclopropane or oxetane;
R 124 and R 125 are independently selected from H, alkyl, halogen or haloalkyl, or R 124 and R 125 together with the carbon atom to which they are attached represent a 3-6 membered cycloalkyl or heterocycloalkyl ring, for example cyclopropane or oxetane;
g is phenyl or a 5-or 6-membered heteroaryl ring, and
Z is CH 2 or c=o.
In any aspect or embodiment described herein, at least one of:
R 101 is H, F or Cl;
R 102 is H, CH 3 or CF 2 H;
R 103 is H or F;
R 104 is H, CH 3, F, or CN;
R 105 is H, CN, CH 3 or CF 3;
R 106 and R 107 are each independently H, F or CH 3;
R 108 is H, F or CH 3 O;
R 109 and R 110 are each independently H or CH 3;
r 111 and R 112 are each independently H, F or CH 3;
r 113 and R 114 are each independently H or CH 3;
R 115 is H or CH 3;
R 116 and R 117 are each independently H or CH 3;
r 118 and R 119 are each independently H, CH 3, F, or R 118 and R 119, together with the carbon atom to which they are attached, represent a cyclopropane or oxetane ring;
R 120 and R 121 are each independently H or CH 3;
R 122 and R 123 are each independently H or CH 3;
R 124 and R 125 are each independently H, CH 3, F, or R 124 and R 125, together with the carbon atom to which they are attached, represent a cyclopropane or oxetane ring;
R 126 and R 127 are each independently H or CH 3;
A is pyridine or pyrimidine;
Z is CH 2 or C=O, or
A combination thereof.
In any aspect or embodiment described herein, the compound is selected from (2S, 4R) -1- ((S) -14- (5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yloxy) -2-tert-butyl-4-oxo-6, 9, 12-trioxa-3-azatetradecane) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (1), 4- (2- (2- (2- (2- (5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yloxy) ethoxy) ethylamino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (2), 4- (2- (2- (5- (5H-pyrido [4,3-b ] indol-7-yl) 2-yloxy) ethoxy) ethyl) amino) -2- (2- (2- (2- (5H-pyrido [4,3-b ] indol-2-yloxy) ethoxy) ethyl) 2- (2- (2- (2- (5H-pyrido [4,3-b ] indol-7-yl) 2-yloxy) ethoxy) ethyl) 2- (2- (2, 6-dioxo-pyrido-3-yl) ethoxy) indoline-2- (4, 3-dioxo-pyrido-3-dione (2) 7-yl) pyridin 2-yloxy) -3,6,9, 12-tetraoxatetradecylamino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (4); (2S, 4R) -1- ((S) -2- (2- (2- (5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yloxy) ethoxy) acetamido) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (5); (2S, 4R) -1- ((S) -17- (5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yloxy) -2-tert-butyl-4-oxo-6, 9,12, 15-tetraoxa-3-aza-heptadecane) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (5); 2S, 4- ((1- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yloxy) -2-yl ] pyrimidine (2S, 4-yl) 1- ((2S, 4-yl) benzo [ 4-yl) pyrimidine-1- (4-yl) 2-yl) benzyl) Piperazine-1-yl) -2- (tert-butyl) -4-oxo-6, 9, 12-trioxa-3-aza-tetradecyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (7); (2S, 4R) -1- ((S) -2-tert-butyl-15- (2- (4- (dimethylamino) phenyl) quinolin-6-yloxy) -4-oxo-6, 9, 12-trioxa-3-aza-pentadecane) -4-hydroxy-N- (4- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (8); (2S, 4R) -1- ((S) -2-tert-butyl-18- (2- (4- (dimethylamino) phenyl) quinolin-6-yloxy) -4-oxo-6, 9,12, 15-tetraoxa-3-aza-octadecane) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (9, 14- ((2S, 4-oxa-2-carboxamide) Imidazo [1,2-a ] pyrimidin-2-yl) -piperazin-1-yl) -2- (tert-butyl) -4, 14-dioxo-6, 9, 12-trioxa-3-azatetradecanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (10); (2S, 4 r) -1- ((S) -14- (4- (benzo [4,5] imidazo [1,2-a ] pyrimidin-2-yl) piperazin-1-yl) -2- (tert-butyl) -4-oxo-6, 9, 12-trioxa-3-azatetradecanoyl) -4-hydroxy-N- (4- (4-methyl oxazol-5-yl) benzyl) pyrrolidine-2-carboxamide (11); (2S, 4 r) -1- ((S) -17- (4- (benzo [4,5] imidazo [1,2-a ] pyrimidin-2-yl) piperazin-1-yl) -2- (tert-butyl) -4-oxo-6, 9, 12-trioxa-3-azatetradecanoyl) -4-hydroxy-N- (4- (4-methyl oxazol-5-yl) benzyl) pyrrolidine-2-carboxamide (11); (2S, 4 r) -17- (benzo [1,2-a ] pyrimidin-2-yl) piperazin-1-yl) -2-yl } Amine (12), 1- ((S) -14- (4- (benzo [4,5] imidazo [1,2-a ] pyrimidin-2-yl) piperazin-1-yl) -2- (tert-butyl) -4, 14-dioxo-6, 9, 12-trioxa-3-azatetradecanoyl) -4-hydroxy-N- (4- (4-methyl oxazol-5-yl) benzyl) pyrrolidine-2-carboxamide (13), 2S, 4R) -1- ((S) -17- (4- (benzo [4,5] imidazo [1,2-a ] pyrimidin-2-yl) piperazin-1-yl) -2- (tert-butyl) -4, 17-dioxo-6, 9,12, 15-tetraoxa-3-azaheptadecanoyl) -4-hydroxy-N- (4- (4-methyl oxazol-5-yl) benzyl) pyrrolidine-2-carboxamide (14), and (2S, 4R) -1- ((S) -14- (4- (benzo [1,2-a ] pyrimidin-2-yl) piperazin-1-yl) -2- (tert-butyl) -4, 17-dioxo-6, 9,12, 15-tetraoxa-3-azaheptadecanoyl) -4-hydroxy-N- (4- (4-methyl oxazol-5-yl) benzyl) pyrrolidine-2-carboxamide (14) (2S, 4R) -1- ((S) -17- (4- (benzo [4,5] imidazo [1,2-a ] pyrimidin-2-yl) piperazin-1-yl) -2- (tert-butyl) -4-oxo-6, 9,12, 15-tetraoxa-3-aza-heptadecanoyl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (16); (2S, 4R) -1- ((S) -14- (4- (benzo [4,5] imidazo [1,2-a ] pyrimidin-2-yl) piperazin-1-yl) -2- (tert-butyl) -4, 14-dioxo-6, 9, 12-trioxa-3-aza-tetradecanoyl) -4-hydroxy-N-, a process for preparing N- (4-methylthiazol-5-yl) phenyl) pyrrolidine-2-carboxamide (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (17); (2S, 4R) -1- ((S) -17- (4- (benzo [4,5] imidazo [1,2-a ] pyrimidin-2-yl) piperazin-1-yl) -2- (tert-butyl) -4, 17-dioxo-6, 9,12, 15-tetraoxa-3-aza-heptadecanoyl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (18); (2S, 4R) -1- ((S) -14- (4- (benzo [4,5] imidazo [1,2-a ] pyrimidin-2-yl) piperazin-1-yl) -2- (tert-butyl) -4-oxo-6, 9, 12-trioxa-3-aza-tetradecanoyl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (18); (2S, 4) -1- (4-methylthiazol-5-yl) phenyl) pyrrolidin-2-carboxamide (19) And [4,5] imidazo [1,2-a ] pyrimidin-2-yl) piperazin-1-yl) -2- (tert-butyl) -4-oxo-6, 9,12, 15-tetraoxa-3-azaheptadecanoyl) -4-hydroxy-N- ((S) -1- (4- (4-methyl oxazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (20); (2S, 4R) -1- ((S) -14- (4- (benzo [4,5] imidazo [1,2-a ] pyrimidin-2-yl) piperazin-1-yl) -2- (tert-butyl) -4, 14-dioxo-6, 9, 12-trioxa-3-azatetradecanoyl) -4-hydroxy-N- ((S) -1- (4-methyl oxazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (21); (2S, 4R) -17- (4- (benzo [4,5] imidazo [1,2-a ] pyrimidin-1-yl) piperazin-1-yl) -2- (tert-butyl) -4, 14-dioxo-6, 12-trioxa-3-azatetradecanoyl) -4-hydroxy-N- ((S) -1- (4-methyl oxazol-5-yl) phenyl) pyrrolidine-2-carboxamide (21); 2S) -17- (4- (benzo [4,5, 2-a ] imidazo [ 1-2-yl) pyrimidin-2-yl) -piperazin-1-yl (21 (S) -1- (4- (4-Methyloxazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (22); (2S, 4R) -1- ((S) -17- (4- (benzo [4,5] pyrimidin-2-yl) piperazin-1-yl) -2- (tert-butyl) -4-oxo-6, 9,12, 15-tetraoxa-3-azaheptadecanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (23); (2S, 4R) -1- ((S) -17- (4- (benzo [4,5] imidazo [1,2-a ] pyrimidin-2-yl) piperazin-1-yl) -2- (tert-butyl) -4, 17-dioxo-6, 9,12, 15-tetraoxa-3-azaheptadecanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (23); (2S, 4- ((S) -1- ((S) -17- (4- (benzo [1,2-a ] pyrimidin-2-yl) piperazin-1-yl) 2- (tert-butyl) -4, 17-dioxo-6, 9, 15-tetraoxa-3-azaheptadecanoyl) benzyl) pyrrolidine-2-carboxamide (24- (2- (2-imidazo [1,2-a ] piperazin-2-yl) Amino) ethoxy) ethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (25), 4- ((14- (4- (benzo [4, 2-a ] pyrimidin-2-yl) piperazin-1-yl) -3,6,9, 12-tetraoxatetradecyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (26), 2S, 4R) -1- ((S) -2- (2- (2- (2- (2- (4- (dimethylamino) phenyl) quinolin-6-yloxy) ethoxy) acetamido) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (27), 2S, 4R) -1- ((S) -2- (2- (2- (2- (4- (dimethylamino) phenyl) quinolin-6-yloxy) ethoxy) acetyl) -3-2-carboxamide (27), 2S, 4- ((S, 4) -2- (2- (2- (4- (4-dimethylamino) phenyl) quinolin-6-yl) oxy) ethoxy) acetyl) -3-2-carboxamide (3, 2-methyl) ethoxy) hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (28); (2S, 4R) -1- ((S) -2-tert-butyl-14- (2- (4- (dimethylamino) phenyl) quinolin-6-yloxy) -4-oxo-6, 9, 12-trioxa-3-aza-tetradecane) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (29); (2S, 4R) -1- ((S) -2-tert-butyl-14- (2- (4- (dimethylamino) phenyl) quinolin-6-yloxy) -4-oxo-6, 9, 12-trioxa-3-aza-tetradecane) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (30); (2S, 4R) -2-tert-butyl-17- (2- (dimethylamino) phenyl) quinolin-6-9-yloxy) 6-yloxy) -4-oxo-6, 9,12, 15-tetraoxa-3-aza-heptadecane) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (31); (2S, 4R) -1- ((S) -2-tert-butyl-17- (2- (4- (dimethylamino) phenyl) quinolin-6-yloxy) -4-oxo-6, 9,12, 15-tetraoxa-3-aza-heptadecane) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (32); (2S, 4R) -1- ((S) -2- (2- (4- (dimethylamino) phenyl) quinolin-6-yloxy) butoxy) acetamido) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2 (2S, 4R) -1- ((S) -2- (2- (4- (2- (4- (dimethylamino) phenyl) quinolin-6-yloxy) butoxy) acetamido) -3, 3-dimethylbutyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (34), (2S, 4R) -1- ((S) -2- (2- (3- (3- (2- (4- (dimethylamino) phenyl) quinolin-6-yloxy) propoxy) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (35), (2S, 4R) -1- ((S) -2- (2- (3- (3- (4- (dimethylamino) phenyl) quinolin-6-yloxy) propoxy) acetamido) -3, 3-dimethylbutyryl) -4-hydroxy -N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (36); (2S, 4R) -1- ((S) -2- (2- (5- (2- (4- (dimethylamino) phenyl) quinolin-6-yloxy) pentyloxy) acetamido) -3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (37); (2S, 4R) -1- ((S) -2- (2- (5- (2- (4- (dimethylamino) phenyl) quinolin-6-yloxy) pentyloxy) acetamido) -3, 3-dimethylbutyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (38); (2S, 4R) -1- ((S) -2-tert-butyl-18- (2- (4- (dimethylamino) phenyl) quinolin-6-yloxy) 4-oxo-6, 9,12, 15-tetraoxa-3-azaoctadecane) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (39), 4- (15- (2- (4- (dimethylamino) phenyl) quinolin-6-yloxy) -3,6,9, 12-tetraoxapentadecylamino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (40), 4- ((2- (2- (2- (2- (4- (benzo [4,5] imidazo [1,2-a ] pyrimidin-2-yl) piperazin-1-oxyethoxy) ethoxy) ethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (41), 4- ((14- (4- (benzo [4,5] imidazo [1,2-a ] pyrimidin-1-2-oxo) -piperazin-3-oxo) -6-oxo-1, 3-dione (41), 4- ((14- (4- (benzo [4,5] imidazo [1,2-a ] pyrimidin-1-yl) -2-oxoethoxy) piperazin-1, 3-dione) 1, 3-dione (42); (2S, 4R) -1- ((2S) -2-tert-butyl-15- (2- (4- (dimethylamino) phenyl) quinolin-6-yloxy) -14-hydroxy-4-oxo-6, 9, 12-trioxa-3-aza-pentadecane) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (43); 4- (2- (2- (2- (3- (2- (4- (dimethylamino) phenyl) quinolin-6-yloxy) propoxy) ethoxy) ethylamino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (44); 4- (15- (2- (4- (dimethylamino) phenyl) quinolin-6-yloxy) -14-hydroxy-3, 6,9, 12-tetraoxapentadecanylamino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3- (2S, 45- ((2, 18-di-butyl) -2- (2S-2- (4-dimethylamino) phenyl) quinolin-3-yl) ethoxy) By-6-yloxy) -17-hydroxy-4-oxo-6, 9,12, 15-tetraoxa-3-azaoctadecane) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide (46), 4- (2- (2- (3- (2- (dimethylamino) phenyl) quinolin-6-yloxy) -2-hydroxypropoxy) ethoxy) ethylamino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (47), 2- (2, 6-dioxopiperidin-3-yl) -4- (14- (5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yloxy) -3,6,9, 12-tetraoxatetradecylamino) isoindoline-1, 3-dione (48), 3- (4- (5- (5H-pyridin-3-yl) indol-3-yl) isoindoline-1, 3-dione (48), 3- (4- (5-H-pyrido [4,3-b ] indol-7-yl) amino) -4- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) isoindoline-1, 3-dione (48) 2, 6-dione (49), 3- (4- (14- (5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yloxy) -3,6,9, 12-tetraoxatetradecyloxy) -1-oxoisoindol-2-yl) piperidine-2, 6-dione (50), 5- ((14- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (51), 5- ((5- (4- (2- (3- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) propoxy) piperazin-1-yl) pentyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (52); 5- (4- (3- ((1 s,3 s) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxybutyloxy) propyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (53), 5- ((5- (4- (3- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) propyl) piperazin-1-yl) pentyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (54), 5- (3- (6- (4- (3- (5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) propyl) pyridin-3-yloxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1-yl) isoindoline-2- ((2, 6-dioxopiperidin-3-1-yl) dione, 5- ((3, 5-3-oxo) indoline-1, 3- ((3-yl) pentyl) 2- (5-3- (3-pyrido-3-yl) indoline) Phenyl) pyridin 2-yl) oxy) cyclobutoxy) ethyl) piperazin-1-yl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (56), 5- ((14- (4- (5H-pyrido [4,3-b ] indol-7-yl) piperidin-1-yl) -3,6,9, 12-tetraoxatetradecyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (57), 5- ((5- (2- (4- (3- (5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) propyl) piperazin-1-yl) ethoxy) pentyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (58), 5- ((5- (4- ((1 r,3 r) -3- (5H-pyrido [4,3-b ] pyridin-2-yl) 2-oxo) piperazin-1-dione (57), 5- ((5- (2 r,3 r) -3H-pyrido-5-2-yl) 2-oxo) piperazin-1-yl) ethoxy) pentyl) Oxopiperidin-3-yl) isoindoline-1, 3-dione (59), 5- (4- (3- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) propyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (60), 2- (2, 6-dioxopiperidin-3-yl) -5- ((5- (4- (3- (5- (5- (2, 2-trifluoroethyl) -5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) propyl) piperazin-1-yl) oxy) isoindoline-1, 3-dione (61), 3- (5- (4- (5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) propyl) 2-oxo) piperazin-1, 62-2-oxo) 1-piperidyl) isoindoline-1, 6-dione 3-yl) -5- ((5- (4- (3- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) -3- (trifluoromethyl) pyridin-2-yl) propyl) piperazin-1-yl) oxy) isoindoline-1, 3-dione (63), 5- (4- (3- ((5 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) propyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (64), 5- ((5- (4- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) piperidin-1-yl) oxy) -2- (2, 6-dioxopiperidin-1-yl) pyridin-1-yl) propyl), 5- ((5- (1 r, 6-dioxopiperidin-1-yl) 1-dione (64) - (5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclobutoxy) piperidin-1-yl) -piperazin-1-yl-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (66), 2- (2, 6-dioxopiperidin-3-yl) -5- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) -3- (trifluoromethyl) pyridin 2-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) isoindoline-1, 3-dione (67), 2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) piperazin-1-yl), and 2- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) piperazin-1-yl-1, 6-dihydro-1, 3- ((3-yl) pyrido-1, 6-1- ((3-methyl-5-pyrido [4,3-b ] pyridin-7-yl) oxy) o-1-pyrido Indol-7-yl) -4- (trifluoromethyl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) isoindoline-1, 3-dione (69), 2- (2, 6-dioxopiperidin-3-yl) -5- (2- (2- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) ethoxy) isoindoline-1, 3-dione (70), 2- (2, 6-dioxopiperidin-3-yl) -5- ((15- (5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) -3,6,9, 12-tetraoxapentadec-14-yn-1-yloxy) isoindoline-1, 3-dione (71), 5- ((5-pyrido [4,3-b ] indol-2-yl) ethoxy), and 2- (2, 6-dioxopiperidin-3-yl) -5- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) isoindoline-1, 3-dione (71), 5- (5-oxo) pyrido [4,3-b ] indol-2-yl) oxy) ethoxy ) -4,6, 7-trifluoroisoindoline-1, 3-dione (72) [5- ((3- (5- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclo-butoxy) pyridin 2-yl) prop-2-ynyl-oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione ] (73); 2- (2, 6-dioxopiperidin-3-yl) -5- ((15- (5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) -3,6,9, 12-tetraoxapentadecyl) oxy) isoindoline-1, 3-dione (74); 2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) pentyl) 2- (5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) 2-oxy) pentyl) 2- (5-oxo) indol-1, 3-yl) 2-dione ] pentyl) isoindoline-1- (3-oxo) 3-dione - (3- (5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) prop-2-yn-1-yl) piperazin-1-yl) prop-2- (4- (6- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclobutoxy) pyridin 2-yl) prop-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (77), 2- (2, 6-dioxopiperidin-3-yl) -5- (4- (6- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclobutoxy) piperazin-1-yl), and 2- (5- (5-pyrido-5- ((5-3-7-yl) pyridin 2-yl) oxy) 1-2-yl) propano-2- (2, 6-dioxopiperidin-1, 3-dione (77) -5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yloxy) pentyl) oxy) azetidin-1-yl-isoindoline-1, 3-dione (79), 2- (2, 6-dioxopiperidin-3-yl) -5- ((1- (5- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) pentyl) azetidin-3-yl) oxy) isoindoline-1, 3-dione (80), 5- ((5- (5H-pyrido [4,3-b ] indol-7-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione (81), 2- (2, 6-dioxo-piperidin-3-yl) -2- ((3-yl) pyridin-1, 3-dione (81), and 2- (2, 6-dioxo-3-2-yl) pyridin-1, 3-dione (80) Oxy) cyclopiperidin-1-yl) pentyl) oxy) isoindoline-1, 3-dione (82), 5- ((5- (5- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin-2-yl) pentyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (83), 2- (2, 6-dioxopiperidin-3-yl) -5- ((6- (3- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) phenoxy) hexyl) oxy) isoindoline-1, 3-dione (84), 2- (2, 6-dioxopiperidin-3-yl) -5- ((1 r,3 r) -3- ((5- ((5-dioxopiperidin-3-yl) 5- ((5-oxo) 5- ((5-pyrido [4,3-b ] indol-7-yl) oxy) cyclopentyl) oxy) isoindoline-1, 3- ((1, 6-dioxopiperidin-3-yl) 5- ((5- ((5-oxo) 5-pyrido [ 4-b ] pyrido ] 7-yl) oxy) pentyl) ) Isoindoline-1, 3-dione (85), 4- ((14- (4- (5H-pyrido [4,3-b ] indol-7-yl) phenoxy) -3,6,9, 12-tetraoxatetradecyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (86), 6- ((14- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) -1H-pyrrolo [3,4-c ] pyridin-1, 3 (2H) -dione (87), 2- (2, 6-dioxopiperidin-3-yl) -5- ((5- (5- (2, 2-trifluoroethyl) -5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxa-ridin-1, 3- (2, 3-c ] pyridin-1, 3 (87), 2- (2, 6-dioxopiperidin-3-yl) 5- ((5- (5, 2-trifluoroethyl) indol-7-yl) oxy) 2-pyrido-3, 3-oxo) -3, 3-dioxo [3,4-c ] pyridin-3-yl ] pyrido-3-yl (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) pentyl) oxy) ethoxy) propyl) piperidin-1-yl) isoindoline-1, 3-dione (89), 2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((4- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) but-2-yn-1-yl) oxy) butoxy) isoindoline-1, 3-dione (90), 2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((8- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxybutyloxy) octyl) piperazin-1-yl) isoindoline-1, 3-1-yl) Diketones (91), 5- ((14- ((3-chloro-5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) ethoxy) pentyl) oxy) -2- (2, 6,9, 12-tetraoxatetradecyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (92), 5- ((5- (2, 2-difluoro-2- (5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) ethoxy) oxy) hexyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (93), 2- (2, 6-dioxopiperidin-3-yl) -5- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) 2-oxo) 2-pentanone) 2- (2, 6-dioxopiperidin-3-yl) 3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) 2-oxo) pyrrol-1, 3-dione (94) oxy) pyrrol-1, 3-yl) oxy) isoindoline -yl) -5- ((5- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) pyridin-2-yl) oxy) isoindoline-1, 3-dione (95), 2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((6- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) cyclohexyl) -3- (trifluoromethyl) piperazin-1-yl) isoindoline-1, 3-dione (96), 2- (2, 6-dioxopiperidin-3-yl) -5- ((6- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin) 2-oxy) cyclobutoxy) cyclohex-2-yline) 2-oxo) 1, 3-dione (96), 1-2-oxo-1, 3-pyrrol-yl) isoindoline -3-yl) -5- ((6- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) oxy) isoindoline-1, 3-dione (98); 2- (2, 6-dioxopiperidin-3-yl) -5- ((3- (3- ((5- (1 r,3 r) -3- ((5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclopropoxy) propyl) azetidin-1, 3-dione (99); 2- (2, 6-dioxopiperidin-3-yl) -5- (6- (4- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) 2- ((3-butoxy) 2-indoline) isoindoline-1, 3-dione (3- ((5-1, 3-pyrido) 2-n-yl) 2-1-yl) propan-3-yl) azetidin-3-yl 3- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) -3- (trifluoromethyl) pyridin 2-yl) oxy) cyclopropoxy) propyl) azetidin-3-yl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (101), 2- (2, 6-dioxopiperidin-3-yl) -5- ((6- (6- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclobutoxy) pyridin 3-yl) hex-5-yn-1-yl) oxy) o-isoindoline-1, 3-dione (102), 5- ((14- ((5- (8, 9-difluoro-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) -3, 6-oxo) -3, 9-tetrazino-2- (3-oxo) -3, 3-oxo) -3- (2-oxo) tetrazino-1, 3-dione (102), 6- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3- (2-oxo) tetrazino-2-oxo) -2-oxo-2-oxo) -2-oxo-2-3-oxo-2-oxo-1-dione (102) 3- (3- (3- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) -3- (trifluoromethyl) oxy) pyridin-2-yl) oxy) cyclobutoxy) propoxy) indoline-1, 3-dione (104), 2- (2, 6-dioxopiperidin-3-yl) -5- ((1- (3- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) -3- (trifluoromethyl) oxy) pyridin-2-yl) oxy) cyclobutan-3-yl) oxy) isoindoline-1, 3-dione (105), 2- (2, 6-dioxopiperidin-3-yl) -5- ((5- ((5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-oxy) 2-yl) indol-1-yl) oxy) indoline-1, 106-dione (2, 6-Dioxopiperidin-3-yl) -5- (4- (4- (6- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) hexyl) oxy) isoindoline-1, 3-dione (107) with 2- ((4- ((1 r,3 r) -5- ((6- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) oxy) hexyl) oxy) isoindoline-1, 3-dione (108) with 2- (2, 6-dioxopiperidin-3-yl) -5- ((6- ((4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclohexyl) oxy) isoindoline-1, 3-dione (108) Indoline-1, 3-dione (109), 2- (2, 6-dioxopiperidin-3-yl) -5- ((6- (6- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclobutoxy) pyridin-3-yl) hexyl) oxy) isoindoline-1, 3-dione (110), 2- (2, 6-dioxopiperidin-3-yl) -5- (3- ((3- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) prop-2-yn-1-yl) oxy) azetidin-1, 3-dione (111), 5- ((5- (8, 9-difluoro-5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin-2-yl) prop-2-yn-1-yl) oxy) isoindoline-1, 3-dione (111), and 5- ((5- (8, 9-difluoro-5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) indol-2-yl) -12-oxo-2-oxopiperidine -1, 3-dione (112), 5- ((4-chloro-5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) pentyl) oxy) isoindoline-1, 6,9, 12-tetraoxatetradecyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (113), 2- (2, 6-dioxopiperidin-3-yl) -5- ((5- (4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) pentyl) oxy) isoindoline-1, 3-dione (114), 2- (2, 6-dioxopiperidin-3-yl) -5- ((1- (5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yloxy) 2-azetidino) pentyl) isoindoline-1, 3-dione (115) ) 5- ((2- (4- (4- ((5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) butyl) -2-azaspiro [3.3] heptan-6-yl) oxy) isoindoline-1, 3-dione (116), 2- (2, 6-dioxopiperidin-3-yl) -5- ((3- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cycloprop-2-yn-1-yl) oxy) isoindoline-1, 3-dione (117), 2- (2, 6-dioxopiperidin-3-yl) -5- (3- ((5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) pyridin-3-trifluoro-2-methyl) pyridin-1-yl) oxy) pyridin-2-yl) 2-butan-yl) oxy) 2-n-yl (2S, 4R) -1- ((S) -17- ((5- (5H-pyrido [4,3-b ] indol-7-yl) oxy) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2- (tert-butyl) -4-oxo-6, 9,12, 15-tetraoxa-3-aza-seventaryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (119); (2S, 4R) -1- ((S) -2- (2- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) ethoxy) acetamido-3, 3-dimethylbutyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) pyrrolidine-2-carboxamide (120); (2S) -1- ((S) -20-pyrido [4,3-b ] indol-7-yl ] pyridin-2-yl) ethoxy -yl) oxy) -2- (tert-butyl) -4-oxo-6,9,12,15,18-pentaoxa-3-azaeicosyl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (121); (2S, 4R) -1- ((S) -23- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) -2- (tert-butyl) -4-oxo-6,9,12,15,18,21-hexaoxa-3-azatricoyl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide (122); 2- (2, 6-dioxopiperidin-3-yl) -5- ((5- (4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) -3- (trifluoromethyl) pyridin-2-yl) oxy) cyclo) piperidinyl-i-piperidinyl) i-N-1-piperidinyl) oxy) 1, 3-dione (123), 2- (2, 6-dioxopiperidin-3-yl) -5- ((6- (4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) phenyl) hex-5-yn-1-yl) oxy) isoindoline-1, 3-dione (124), 2- (2, 6-dioxopiperidin-3-yl) -5- (3- (3- (3- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) -3- (trifluoromethyl) pyridin-2-yl) oxy) cyclopropoxy) propoxy) azetidin-1, 3-dione (125), 2- (2, 6-dioxopiperidin-3-yl) -5- ((6- (methyl) -5- (3-amino) pyrido [4,3-b ] indol-7-yl) oxy) propan-1-yl 2-azaspiro [3 ]. 3] heptan-2-yl) pentyl) oxy) isoindoline-1, 3-dione (126); 3- (5- (4- ((1- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) piperidin-4-yl) methyl) piperazin-1-yl) -1-oxoisoindolin-2, 6-dione (127), 3- (5- (4- (2- (5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) piperidin-4-yl) ethyl) piperazin-1-yl) -1-oxoisoindol-2-yl) piperidin-2, 6-dione (128), 2- (2, 6-dioxopiperidin-3-yl) -5- ((1, 1-trifluoro-6- (2- (2- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) ethoxy) hexyl) 2-oxo) 2-oxo) isoindolin-1, 3-dione (129) 2- (2, 6-Dioxopiperidin-3-yl) -5- (3- (3- (4- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) -3- (trifluoromethyl) pyridin-2-yl) oxy) piperidin-1-yl) propoxy) azetidin-1-yl) isoindoline-1, 3-dione (130), 2- (2, 6-dioxopiperidin-3-yl) -5- ((17- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3,6,9,12, 15-pentaoxaheptadecyl) oxy) isoindoline-1, 3-dione (131), 2- (2, 6-dioxopiperidin-3-yl) -5- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) hexahydroindoline-1, 3-dione (130), and 2- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) -hexahydroindoline-1, 3-dione (132) - ((5- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) pentyl) oxy) hexyl) azetidin-1-yl) isoindoline-1, 3-dione (133), 2- (2, 6-dioxopiperidin-3-yl) -5- ((6- (6- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclobutoxy) pyridazin-3-yl) hex-5-yn-1-yl) oxy) isoindoline-1, 3-dione (134), 2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((2- (((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclobutyl) methyl) -2-aza-3-yl) 2-indoline-1, 3-dione (134), and 2- (2, 6-dioxopiperidin-3-yl) 1, 3-dione 5- (4- ((2- ((1 s,3 s) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclobutane-1-carbonyl) -2-azaspiro [3.3] heptan-6-yl) oxy) butoxy) isoindoline-1, 3-dione (136); 2- (2, 6-Dioxopiperidin-3-yl) -5- ((5- (6- (methyl ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutyl) amino) -2-azaspiro [3.3] heptan-2-yl) -5-oxopentyl) oxy) isoindoline-1, 3-dione (137), 5- ((14- ((5- (5- (difluoromethyl) -5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (138), 2- (2, 6-dioxo-piperidin-3-yl) isoindoline (138) Piperidin-3-yl) -5- ((14- ((3-fluoro-5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) isoindoline-1, 3-dione (139), 2- (2, 6-dioxopiperidin-3-yl) -5- ((3-methyl-5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) isoindoline-1, 3-dione (140), 2- (2, 6-dioxopiperidin-3-yl) -5- ((6- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) pyrimidin-2-yl) 2-hexyn-1, 3- (3-diyl) oxy) isoindoline-1, 3-dione (140) ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) -3- (trifluoromethyl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) prop-2-yn-1-yl) azetidin-3-yl) oxy) isoindoline-1, 3-dione (142), 2- (2, 6-dioxopiperidin-3-yl) -5- ((14- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) -6- (trifluoromethyl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) isoindoline-1, 3-dione (143), 2- (2, 6-dioxopiperidin-3-yl) -5- (6- ((1 s,3 s) -3- (5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) indoline-1-3-yl) oxy) isoindoline, 3-dione (144), 2- (2, 6-dioxopiperidin-3-yl) -5- (6- (6- ((1 s,3 s) -3- (5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin-3-yl) hexoxy) isoindoline-1, 3-dione (145), 2- (2, 6-dioxopiperidin-3-yl) -5- ((6- (6- (3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) propoxy) pyridin-3-yl) hex-5-yn-1-yloxy) isoindoline-1, 3-dione (146), 2- (2, 6-dioxopiperidin-3-yl) -5- ((6- (1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yloxy) isoindoline (147), 2- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) indol-1-yl) isoindoline-1, 3-dione (147) 3- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) -3- (trifluoromethyl) pyridin 2-yl) oxy) cyclobutoxy) propoxy) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (148), 2- (2, 6-dioxopiperidin-3-yl) -5- ((6- (6- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin 2-yl) oxy) cyclohexyl) pyridazin-3-oxy) isoindoline-1, 3-dione ] (149), 5- (6- (2, 2-difluoro-5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-oxy) cyclopentyl) isoindoline-1, 3-dione ] (149), 2- (6-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) 2-oxo) indoline-1, 3-dione ] (150); 2- (2, 6-Dioxopiperidin-3-yl) -5- ((6- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyrimidin-2-yl) oxy) isoindoline-1, 3-dione (151), 2- (2, 6-dioxopiperidin-3-yl) -5- ((1- (3- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) prop-2-yn-3-yl) oxy) isoindoline-1, 3-dione (152), 2- (2, 6-dioxopiperidin-3-yl) -5- (3, 3-trifluoro-2-r) -5- ((3, 3-trifluoro-2-7-yl) pyridin-5- ((5-methyl-5H-pyrido [ 4-b ] indol-7-yl) oxy) pyridin-2-yl) oxy) isoindoline-1, 3-dione (152) ) Propyl) azetidin-1-yl) isoindoline-1, 3-dione (153), 2- (2, 6-dioxopiperidin-3-yl) -5- (3- (2, 2-trifluoro-1- ((6- ((1 r,3 r) -3- ((5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclobutoxy) ethyl) azetidin-1, 3-dione (154), 2- (2, 6-dioxopiperidin-3-yl) -5- (3- ((5- (2- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) pyridin-2-yl) azetidin-1-yl) isoindoline-1, 3-dione (155), 2- (2, 6-dioxo-piperidin-3-yl) -5- ((5- (2- ((5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) pyridin-2-yl) isoindoline-1, 3-dione (155), 2- (2, 6-dioxo-piperidin-3- (3-methyl-3-yl) -3- ((3-pyrido [4, 3-H-pyrido-1-yl) oxy) pyridin-2-yl) oxy 2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((2 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutane-1-carbonyl) -2-azaspiro [3.3] heptan-6-yl) oxy) isoindoline-1, 3-dione (157), 2- (2, 6-dioxopiperidin-3-yl) -5- (2- ((6- (4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) piperidin-1-yl) oxy) isoindoline-1, 3-dione (157), 2- (2, 6-dioxopiperidin-3-yl) -5- (2- ((6- (1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) cyclobutoxy) piperidin-1-yl) oxy), and 2- (3-oxo) 2- (3, 3-oxo) piperidin-1-2-yl) 2-oxo) 6- (3-oxo) 6-1-dione (158) ) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclobutoxy) pyridin 2-yl) prop-2-yn-1-yl) oxy) azetidin-1, 3-dione (159), 2- (2, 6-dioxopiperidin-3-yl) -5- (3- (3- ((5 s,3 s) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclobutoxy) pyridin 2-yl) propoxy) azetidin-1, 3-dione (160), 2- (2, 6-dioxopiperidin-3-yl) -5- (3- (2- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin) 2-ethoxy) cyclobutoxy) ethoxy) 2-indoline-1, 3-dione (160) Heterocyclobutane-1-yl) isoindoline-1, 3-dione (161), 2- (2, 6-dioxopiperidin-3-yl) -5- (3- (4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxybutyloxy) cyclobutoxy) azetidin-1-yl) isoindoline-1, 3-dione (162), 2- (2, 6-dioxopiperidin-3-yl) -5- (3- (2- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxybutyloxy) ethoxy) azetidin-1, 3-dione (163), 5- (6- ((1 r,3 r) -3- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-oxybutyloxy) -2-piperidyl) 1, 3-dione 3-yl) isoindoline-1, 3-dione (164); 5- ((5- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutan-1-yl) piperidin-4-yl) oxy) pentyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (165), 5- ((1 s,3 s) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutan-4-yl) oxy) pentyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (166), 2- (2, 6-dioxopiperidin-3-yl) 5- (3- ((3- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) pyridin-2-yl) propoxy) 2-propoxy) 1-yl) oxy) azetidin-1-yl isoindoline-1, 3-dione (167), 2- (2, 6-dioxopiperidin-3-yl) -5- (3- (3- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) propoxy) pyridin-2-yl) propoxy-1-yl) isoindoline-1, 3-dione (168), 2- (2, 6-dioxopiperidin-3-yl) -5- (3- ((3- (((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) methyl) cyclobutoxy) cyclobutane1-yl) isoindoline-1, 3-dione (168), 2- (2, 6-dioxopiperidin-3-yl) -5- (3- ((3- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) methyl) azetidin-1-yl) isoindoline-1-dione (169), and 2- (3-dioxo-3- (3-methyl) -3- (3-s) -3-pyrido [ 3-yl) pyrido-3-yl) methoxy) piperidine-169 b ] indol-7-yl) oxy) cyclobutoxy) propoxy-1, 3-isoindoline-1, 3-dione (170), 5- ((4, 4-difluoro-5- (4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) piperidin-1-yl) pentyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (171), 5- ((6- ((5- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) pyridin-2-yl) hex-5-yn-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3- ((3- ((3 r) -3- ((5- (5H-pyrido [1, 3-b ] indol-7-yl) oxy) pyridin-2-yl) hex-5-yn-2-yl) oxy), and 3- ((2, 6-dioxopiperidin-3-yl) isoindoline-1, 3- (3-yl) oxy) 3- ((3-pyrido-3-yl) 3-oxo) pyrido ) Cyclobutoxy) pyridin-2-yn-1-yl) oxy) prop-2- (2, 6-dioxopiperidin-3-yl) ethoxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (173), 2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((3- (((1 r,3 r) -3- ((5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclobutoxy) methyl) bicyclo [1.1.1] pent-1-yl) methoxy) isoindoline-1, 3-dione (174), 2- (2, 6-dioxopiperidin-3-yl) -5- ((3- (3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) azetidine-1-carbonyl) bicyclo [1.1.1] pent-1-yl) methoxy) pentyl) 2- (3, 3- ((3-fluoro) 3-dione (3, 3- ((3-5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) azetidine-1-carbonyl) methoxy) 1- (3, 3-fluoro) 1,3- ((3-dioxo) 3-1-2-dioxo) methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclobutoxy) propoxy-1-oxoisoindol-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (176), 3- (5- (3- ((3- (1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) oxy) cyclobutan-1-yl) -1-oxoisoindol-2-yl) piperidin-2, 6-dione (177), 2- (2, 6-dioxopiperidin-3-yl) -5- (3- (((6- ((1 r,3 r) -3- ((5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) cyclobutan-1-yl) oxetan-methyl group 1, 3-dione (178), 2- (2, 6-dioxopiperidine-3-yl) -5- (2- ((3- (5- ((1 r,3 r) -3- ((5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) prop-2-yn-1-yloxy) ethoxy) isoindoline-1, 3-dione (179), 3- (5- ((3- (5- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin-2-yl) prop-2-yn-1-yl) oxy) -1-oxoisoindolin-2, 6-dione (180), 2- (2, 6-dioxopiperidin-3-yl) -5- (3- (2, 5- ((3 r) -3- ((5-methyl-3-7-yl) pyrido ] pyridin-2-yl) oxy) prop-2-yn-1-yl, 6-dione (180), 3- (5- ((1 r,3 r) -3- ((5-methyl-3-7-yl) pyrido ] pyridin-2-yl) oxy) propan-1-oxy Pentyl) oxy) ethyl) azetidin-1-yl) isoindoline-1, 3-dione (181), 5- (3- (3- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) propoxy) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (182), 5- ((3- (5- ((1 s,3 s) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin 2-yl) prop-2-yn-1-yl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (183), 2- (2, 6-dioxopiperidin-3-yl) -5- (3- (3-methyl) indol-7-3- ((5H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin 2-yl) prop-2-yn-1-dione (183), and 5- ((2, 6-dioxopiperidin-3-yl) 5- (3-yl) isoindoline-1, 3-dione (3) Bicyclo [1.1.1] penta-1-yl) heptyloxy) isoindoline-1, 3-dione (184); (2S, 4R) -N- (2- ((5- (5H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin 2-yl) ethoxy) -4- (4-methylthiazol-5-yl) benzyl) -4-hydroxy-1- ((S) -3-methyl-2- (1-oxoisoindolin-2-yl) butyryl) pyrrolidine-2-carboxamide (185); (2S, 4R) -N- (2- (2- ((5- (5H-pyrido [4,3-b ] indol-7-yl) oxy) ethoxy) -4- (4-methylthiazol-5-yl) benzyl) -4-hydroxy-1- ((S) -3-methyl-2- (1-oxoisoindolin-2-carboxamide (186); (2S, 4R) -N- (2- (2- (5H-pyrido [4,3-b ] indol-7-yl) oxy) ethoxy) 4-hydroxy-1- ((S) -3-methyl-2- (1-oxoisoindolin-2-yl) pyrrolidine-2-carboxamide (186); (2S, 4R) -N- (2- (2-H-pyrido [4,3-b ] indol-7-yl) oxy) ethoxy) -7-yl) pyridin-2-yl) oxy) ethoxy) -4- (4-methylthiazol-5-yl) benzyl) -4-hydroxy-1- ((S) -3-methyl-2- (1-oxoisoindolin-2-yl) butanoyl) pyrrolidine-2-carboxamide (187), 5- (2- ((3- (4- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) phenyl) prop-2-yn-1-yl) oxy) ethoxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (188), 5- ((3- (4- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxybutyloxy) phenyl) prop-2-yn-1-yl) oxy) -2- (2, 6-dioxo-piperidin-3-yl) isoindoline (188), 5- ((3- (4 r, 3-b) indol-7-yl) pyridin-2-yl) cyclobutoxy) phenyl) prop-2- (2, 6-dioxo-1-2-yl) 1-dione (189) Piperidin-3-yl) -5- (3- (2- (2- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) ethoxy) ethyl) azetidin-1-yl) isoindoline-1, 3-dione (190); 2- (2, 6-dioxopiperidin-3-yl) -5- (3- ((3- (2- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin-2-yl) oxy) cyclobutoxy) ethoxy) propoxy) methyl) azetidin-1-yl) isoindoline-1, 3-dione (191); 2- (2, 6-dioxopiperidin-3-yl) -5- (3- ((2- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin-1-yl) oxetan ethoxy) azetidin-1-yl) ethoxy 1, 3-diones (192), 2- (2, 6-dioxopiperidin-3-yl) -5- (3- (3- (2- (6- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) -2-azaspiro [3.3] heptan-2-yl) -2-oxoethoxy) propoxy) azetidin-1-yl) isoindoline-1, 3-dione (193), 5- (3- ((3- (5- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin-2-yl) prop-2-yn-1-yl) oxy) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (194), 5- ((3- (5- ((1 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin-2-yl) prop-2-yn-1-yl) oxy) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (194), 5- ((4-chloro-5- (4-methyl-5H-pyrido-7-yl) oxy) pyridin-2-yl) oxy) pyridin-2-yl (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (195) (2S, 4R) -N- (2- (2- (2- (2- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) ethoxy) -4- (4-methylthiazol-5-yl) benzyl) -4-hydroxy-1- ((S) -3-methyl-2- (1-oxoisoindolin-2-yl) butyryl) pyrrolidine-2-carboxamide (196), 5- (6- ((2, 2-difluoro-5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclobutoxy) pentyl) oxy) -2-azaspiro [3.3] heptane-2-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (197), 2- (2, 6-dioxopiperidin-3-yl) -5- ((5- (3, 3-fluoro-5- ((5-methyl) -5- ((3-7-yl) cyclobutoxy) oxy) cyclopentyl) oxy) 2-azaspiro [ 3.3-3-yl ] heptane-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (197) Pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclobutoxy) piperidin-1-yl) phenyl) prop-2-yn-1-yl) oxy) isoindoline-1, 3-dione (198); 3- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) methyl) -N-methyl-N- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yloxy) cyclobutyl) bicyclo [1.1.1] pentane-1-carboxamide (199); 2- (2, 6-dioxopiperidin-3-yl) -5- (3- ((7- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclobutoxy) azetidin-1, 3-dione (200); 2S, 4R) -N- (2- ((5- (5H-pyridin-7-yl) pyridin-2-yl) cyclobutoxy) azetidin-1, 3-dione (200) And [4,3-b ] indol-7-yl) pyridin 2-yloxy) -3,6,9, 12-tetraoxatetradecyl) oxy) -4- (4-methylthiazol-5-yl) benzyl) -4-hydroxy-1- ((S) -3-methyl-2- (1-oxoisoindolin-2-yl) butyryl) pyrrolidine-2-carboxamide (201), 2- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidin-3-yl) methoxy) -N-methyl-N- (3- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) propyl) acetamide (202), 2- ((14- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) oxy) -3, 3-dioxo-5-yl) azetidin-3, 3-methyl-N- (3- ((1 r,3 r) -3-pyrido-5-yl) pyrido [4, 3-H-pyrido-7-yl) oxy ] cyclobutoxy) acetamide (202), and 2- ((14- ((2- (2, 6-dioxopiperidin-3-yl) 3-dioxo-isoindol-5-yl) oxy) 3-methyl) pyrido-N-yl) 3-yl ] 4-yl (3-yl) amino-N-yl) can be obtained - ((3- (5- ((1 r,3 r) -3- ((5- (8, 9-difluoro-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclobutoxy) pyridin 2-yl) prop-2-yn-1-yl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (204); 2- (2, 6-dioxopiperidin-3-yl) -5- (3- (3- (3- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclobutoxy) piperidin-1-yl) phenyl) propoxy) isoindoline-1, 3-dione (205); 2- (2, 6-dioxopiperidin-3-yl) -5- (3- ((2- (2- ((1 r,3 r) -3- (5-methyl-pyrido [4,3-b ] indol-7-yl) 2-ethoxy) cyclobutoxy) ethoxy -1-yl) isoindoline-1, 3-dione (206), 5- ((14- ((5- (benzo [4,5] imidazo [1,2-a ] pyrimidin-2-yl) pyridin 2-yloxy) -3,6,9, 12-tetraoxatetradecyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (207), 2- (2, 6-dioxopiperidin-3-yl) -5- (2- (2- (2- ((1- (5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) azetidin-3-yl) oxy) ethoxy) isoindoline-1, 3-dione (208), 2- (2, 6-dioxopiperidin-3-yl) -5- (2- ((3- (((1 r,3 r) -3- (5-methyl-5H-pyrido [4,3-b ] indol-1-2-methoxy) ethoxy) 1- ((3- (((1 r,3 r) -3-dioxopiperidin-3-yl) 5- (5-methyl-pyrido-3-yl) indol) 2-yl) ethoxy) 1-2-bicyclo [ 1.1-ethoxy) In-1, 3-dione (209), 2- (2, 6-dioxopiperidin-3-yl) -5- ((15- (4- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) piperazin-1-yl) -3,6,9, 12-tetraoxapentadecyl) oxy) isoindoline-1, 3-dione (210), 2- (2, 6-dioxopiperidin-3-yl) -5- (3- (3- (2- ((6- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -2-azaspiro [3.3] heptan-2-yl) ethoxy) propoxy) azetidin-1-yl) isoindoline-1, 3-dione (211), 2- (2, 6-dioxopiperidin-3-yl) -5- (3- ((4- ((1 r,3 r) -3- (5-methyl-5H-pyrido [ 4-b ] indol-7-yl) pyridin-2-yl) ethoxy) azetidin-1-yl) 2-oxo-2-butano-yl) azetidin-1-yl) isoindoline-1, 3-dione (212), 2- (2, 6-dioxopiperidin-3-yl) -5- (6- (2- (2- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) ethoxy) -2-azaspiro [3.3] heptane-2-yl) isoindoline-1, 3-dione (213), 2- (2, 6-dioxopiperidin-3-yl) -5- (4- (3- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclopropoxy) propyl) piperazin-1, 3-dione (214), 2- (2, 6-dioxopiperidin-3-yl) -5- (3- ((1 r, 3-yl) isoindoline-1, 3-dione (213), 2- (2, 6-dioxopiperidin-3-yl) -5- (3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclopropyloxy) propyl) piperazin-1-yl-dione (214) ) Pyridin 2-yl) oxy) cyclopropoxy) ethoxy) piperidin-1-yl isoindoline-1, 3-dione (216), 2- (2, 6-dioxopiperidin-3-yl) -5- (4- (2- (3- ((1 r,3 r) -3- ((5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) propoxy) piperidin-1-yl) isoindoline-1, 3-dione (216), 2- (2, 6-dioxopiperidin-3-yl) -5- ((1R, 3 r) -3- ((2- (3- ((1 r, 3R) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) propoxy) ethyl) amino) cyclobutoxy) isoindoline-1, 3-dione (217), 2- (2, 6-dioxopiperidin-3-yl) -5- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) 2-yloxy) propoxy) piperidin-1-yl) isoindoline 2-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) isoindoline-1, 3-dione (218), 3- (5- ((3- (5- ((1 r,3 r) -3- ((5- (8, 9-difluoro-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) prop-2-yn-1-yloxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (219), 3- (5- ((3- (5- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) prop-2-yn-1-yl) ethoxy) -1-oxoisoindolin-2, 6-dione (220), 3- ((3- (3 r, 3-pyrido [ 4-b ] indol-7-yl) pyridin-2-yl) oxy) pyridin-2-yl) ethoxy), and 3- ((3, 3-oxy) pyrido [3, 3-b ] indol-1-yl) pyridin-2-yl) oxy) piperidine-2, 6-dione (220) 2-yl) prop-2-yn-1-yl) oxy) azetidin-1-yl) -1-oxoisoindolin-2, 6-dione (221), 3- (5- ((3- (5- ((1 r,3 r) -3- ((5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) prop-2-yn-1-yl) oxy) -1-oxoisoindolin-2, 6-dione (222), 3- (5- ((3- (6- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) pyridin-2-yl) prop-2-oxy) 1-oxoisoindolin-2, 6-dione (223), 3- (3- (3- (3 r, 3-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) prop-2-yl) piperidin-2, 6-dione (223) ) Oxy) cyclobutoxy) pyridin-2-yl) propoxy) prop-1-yn-1-yl) -1-oxoisoindolin-2-yl) -piperidine-2, 6-dione (224), 3- (5- (3- ((3- (5- ((1 r,3 r) -3- ((5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) prop-2-yn-1-yl) oxy) prop-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (225), 3- (5- ((3- ((5- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) pyridin-2-yl) prop-2-yn-1-yl) oxy) -4, 6-difluoro-1-oxoindol-2-yl) piperidin-2, 6-dione (226), 3- ((3- ((3 r,3 r) -3- ((3H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin-2-yl) oxy) prop-4, 6-difluoro-1-oxoindol-2-yl) piperidine-2-yl) [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclobutoxy) prop-2-yn-1-yl) oxy) cyclobutoxy) -1-oxoisoindolin-2-yl piperidine-2, 6-dione (227), 3- (5- (4- (5- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclobutoxy) pyridin 2-yl) prop-2-yn-1-yl) piperazin-1-yl) -1-oxoisoindolin-2, 6-dione (228), 2- ((3- (5- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclobutoxy) pyridin 2-yl) prop-2-yn-1-yl) oxy) -N- (2, 6-dioxo-piperidin-2-yl) piperidine-2, 6-dione (228) 1-oxoisoindolin-5-yl) -N-methylacetamide (229), 3- (5- ((1R, 3 r) -3- ((3- (5- ((1 r, 3R) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin-2-yl) cyclobutoxy) prop-2-yn-1-yl) oxy) cyclobutyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (230), 3- (5- ((3- (6- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) pyridazin-2-yn-1-yl) oxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (231), 3- (5- ((3- ((1 r,3 r) -3- ((5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) prop-2-yn-2-yl) 3- (5- ((3- ((1 r,3 r) -3-pyrido-2-yl) prop-2-yl) 2-yl) 6-dione (231) -1-yl) oxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (232); 3- (5- (2- ((3- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) prop-2-yn-1-yl) oxy) ethoxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (233), 3- ((3- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) prop-2-yn-1-yl) oxy) -1-oxoisoindolin-2, 6-dione (234), 2- ((1 r,3 r) -3- ((6- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxo-5-isoindolin-yl) oxy) indol-2-yl) piperidine-2, 6-dione (234) 1-yn-1-yl) oxy) pyridin-3-yl) oxy) cyclobutoxy) -5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) nicotinonitrile (235), 5- (2- ((3- (5- ((1 r,3 r) -3- ((5- (5- (difluoromethyl) -5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) pyridin-2-yn-1-yl) oxy) prop-2-yn-1-yl) oxy) ethoxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (236), 2- (2, 6-dioxopiperidin-3-yl) -5- (2- ((3- (5- ((1 r,3 r) -3-methyl-5- (5H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin-2-yl) cyclobutoxy) prop-2-yn-1-yl) 2-yn-1, 3-dione (236), 2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (236) - ((6- (3- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) oxy) ethoxy) prop-1-yn-1-yl) pyridin-3-yl) oxy) cyclobutoxy) -5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) nicotinonitrile (238), 3- (5- ((1 r,3 r) -3- ((5- (5- (difluoromethyl) -5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) prop-2-yn-1-yl) oxy) ethoxy) -1-oxoisoindolin-2, 6-dione (239), 3- (5- ((3- ((1 r,3 r) -3- ((3-methyl-5- (5-methyl-5H-pyrido [4,3 b ] indol-7-yl) pyridin-2-yl) cyclobutoxy) pyridin-2-yl) propan-2-yl Phenyl) oxy) ethoxy) -1-oxoisoindolin-2-yl piperidine-2, 6-dione (241), 3- ((3- (3- (4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) piperidin-1-yl) phenyl) prop-2-yn-1-yl) oxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (241), 2- (2, 6-dioxopiperidin-3-yl) -5- ((3- (4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin-2-yl) cyclobutoxy) prop-2-yn-1-yl) oxy) prop-2-yn-1, 3-dione (241), and 3- ((3- (3 r, 3-dioxopiperidin-3-yl) piperidine-3- ((3-4- ((3-1-yl) pyrido-3-yl) pyrido-2-yl) oxy) prop-2-yn-1-yl) oxy) indolin-1, 242 4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) piperidin-1-yl) pyridin-2-yn-1-yl) oxy) -1-oxoisoindolin-2, 6-dione (243), 2- (2, 6-dioxopiperidin-3-yl) -5- ((3- (4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin-2-yl) cyclobutoxy) piperidin-2-yl) pyrimidin-2-yn-1-yl) oxy) isoindolin-1, 3-dione (244), 3- (5- ((3- (4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin-2-yl) cyclobutoxy) piperidin-1-2-yl) piperidin-2-yl) indol-1, 3-dione (244), 3- (4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin-2-yl) piperidin-2-yl) indol-1-yl) 2-yl) indol-2-yl) 1-yl -a diketone (245); 2- (2, 6-Dioxopiperidin-3-yl) -5- ((3- (2- (4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) piperidin-1-yl) pyrimidin-4-yl) prop-2-yn-1-yloxy) isoindoline-1, 3-dione (246), 3- (5- ((3- (2- (4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) piperidin-1-yl) prop-2-yn-1-yl) oxy) -1-oxoisoindol-2-6-dione (247), 2- (2, 6-dioxopiperidin-3-yl) -5- (2- (3 r,3 r) -3- ((5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) prop-2-yn-1-yl) oxy) -1-oxoisoindol-2, 6-dione (247), 2- (2, 6-dioxopiperidin-3-yl) -5- (2- (3-r, 3-dioxopiperidin-3-yl) pyridin-3-yl) 2-yl) pyrido [ 3-yl ] pyridin-7-yl ] 2-yl ) Oxy) cyclobutoxy) piperidin-1-yl) propoxy) ethoxy) isoindoline-1, 3-dione (248), 3- (5- (2- (3- (4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) piperidin-1-yl) propoxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (249), 2- (2, 6-dioxopiperidin-3-yl) -5- ((6- (4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) piperidin-1-yl) hex-yn-2-yn-1-yl) oxy) isoindoline-1, 3-dione (250), 3- ((5- (4 r) -3- (3 r) -3-dioxopiperidin-3-yl) 5- ((6- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin-2-yl) oxy) isoindoline-1, 3-dione (250) Piperidin-1-yl) hex-2-yn-1-yl) oxy) -1-oxoisoindolin-2, 6-dione (251), 2- (2, 6-dioxopiperidin-3-yl) -5- (2- (2- (2- ((3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) azetidin-1-yl) ethoxy) isoindoline-1, 3-dione (252), N- (2- ((1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidin-3-yl) oxy) ethyl) -N-methyl-4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclobutoxy) amine, and 2- (2- (2, 6-dioxo-1- ((3-2, 3-dioxo-isoindolin-3-yl) oxy) ethyl) N-methyl-4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido-pyridin-7-yl) pyridin-2-yl) oxy) cyclobutoxy) amine 3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) piperidin-1-yl) -2-oxoethyl) azetidin-3-yl) oxy) isoindoline-1, 3-dione (254), 2- (2, 6-dioxopiperidin-3-yl) -5- (3- (2- (4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclobutoxy) piperidin-1-yl) -2-oxoethoxy) azetidin-1, 3-dione (255), 2- (2, 6-dioxopiperidin-3-yl) -5- (3- ((3- (3- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) indol-1-yl) 1-dione (256) 1-2-oxoethoxy) azetidin-1-yl) 1-dione (2, 6-Dioxopiperidin-3-yl) -5- (3- (3- (3- (((1 s,3 s) -1-hydroxy-3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutyl) methoxy) propoxy) azetidin-1, 3-dione (257), 2- (2, 6-dioxopiperidin-3-yl) -5- (2- (9- (2- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) ethyl) -1-oxa-4, 9-diazaspiro [5.5] undec-4-yl) ethoxy) isoindoline-1, 3-dione (258), 2- (2, 6-dioxopiperidin-3-yl) -5- (9- (3-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) ethyl) -1-oxa-4, 9-diazaspiro [5.5] undec-4-yl) ethoxy) isoindoline-1, 3-dione (258), 2- (2, 6-dioxopiperidin-3-yl) -5- (3-yl) -3- ((5- (3-methyl-3-yl) pyrido-7-yl) pyrido [ 3-yl ] pyrido [ 3-H-7-yl ] pyrido-1-yl ) Methyl) -1-oxa-4, 9-diazaspiro [5.5] undec-4-yl) but-2-yn-1-yl) oxy) isoindoline-1, 3-dione (259), 2- (2, 6-dioxopiperidin-3-yl) -5- ((3- (3- (4- (((1 s,3 s) -1-hydroxy-3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclobutyl methyl) piperazin-1-yl) phenyl) prop-2-yn-1-yl) oxy) isoindoline-1, 3-dione (260), 2- (2, 6-dioxopiperidin-3-yl) -5- ((3- (4- (((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclobutyl) methyl) propan-1-2-yn) 1-yl) isoindoline-1, 3-dione (261); 2- (2, 6-Dioxopiperidin-3-yl) -5- (2- (3- (3- (((1 s,3 s) -1-hydroxy-3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutyl) methoxy) propoxy) ethoxy) isoindoline-1, 3-dione (262), 2- (2, 6-dioxopiperidin-3-yl) -5- (2- (3- (3- ((3-hydroxy-1- (5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) azetidin-3-yl) methoxy) propoxy) ethoxy) isoindoline-1, 3-dione (263), 2- (2, 6-dioxopiperidin-3-yl) -5- (3- (3- (3- ((5 ' - (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) ethoxy) prop-3 ' -yloxy) ethoxy) isoindoline-1, 3-dione (262), 2- (3- ((5-methyl-5H-pyrido [4,3-b ] indol-7-yl) ethoxy) prop-2 ' -yloxy) ethoxy) isoindoline-1, 3-dione (263) Butane-1-yl) isoindoline-1, 3-dione (264), 5- ((14- ((5- (6, 8-difluoro-5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (265), 2- (2, 6-dioxopiperidin-3-yl) -5- ((14- ((1- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) isoindoline-1, 3-dione (266), 2- (2, 6-dioxopiperidin-3-yl) -5- (3- (2- ((1 r) -3- (2 r, 5-pyrido [4,3-b ] indol-7-yl) oxy) piperidin-4-yl) oxy) isoindoline-1, 3-dione (266), 2- ((1, 3 r) -3- (2-dioxopiperidin-3-yl) 3-1, 267-oxoindol-1, 7-yl) ethoxy ] 1-pyrido [ 4-yl ] butan-7-yl) oxy ] isoindoline ) 2- (2, 6-Dioxopiperidin-3-yl) -5- (3- ((1S, 2R) -2- ((4- ((1 r, 3R) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) methyl) cyclopropyl) azetidin-1-yl) isoindoline-1, 3-dione (268), 2- (2, 6-dioxopiperidin-3-yl) -5- (3- (4- (((1R, 2R) -2- ((1 r, 3R) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutyl) methoxy) azetidin-1, 3-dione (269), 2- (2, 6-dioxopiperidin-3-yl) -5- (3- (2- (((2R, 2- ((1R, 3-methyl) -5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutyl) cyclopropyl) methoxy) azetidin-1, 3-dione (269), 2- (2- (-2- ((2R, 3-dioxopiperidin-3-yl) -5- (2- ((1R, 3-yl) pyrido [2, 3-yl ] pyrido [4, 3-H-pyrido ] 7-yl) oxy) cyclopropyl) ) Oxygen-containing cyclobutyl) cyclopropyl) methoxy) ethoxy) azetidin-1, 3-dione (270), 5- (3- (3- (2, 2-difluoro-3- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) 2-yloxy) cyclobutoxy) ethoxy) azetidin-1, 3-dione (271), 5- (3- (3- (2, 2-difluoro-3- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclopropoxy) propoxy) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) oxy) cyclobutane-1, 3-dione (271), and 5- (3- (3- (3, 3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclopropoxy) propoxy) azetidin-1-yl) Pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxybutyloxy) propoxy) propan-2-yn-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (273), 2- (2, 6-dioxopiperidin-3-yl) -5- (2- ((3- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin 2-yl) cyclobutoxy) propan-2-yn-1-yl) oxy) isoindoline-1, 3-dione (274), 2- (2, 6-dioxopiperidin-3-yl) -5- (2- ((5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) cyclobutoxy) pyridin-1-yl) 2-indoline-1, 3-dione (275) 2-ethoxy) isoindoline-1, 3-yl) 2-butanone -difluoro-3- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclobutoxy) pyridin 2-yl) prop-2-yn-1-yl) oxy) ethoxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (276); 3- (5- ((4- (5- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclobutoxy) pyridin 2-yl) but-3-yn-1-yl) oxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (277); 3- (5- (((3- (5- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) prop-2-yn-1-yl) oxy) methyl) -1-oxoisoindolin-2-yl) piperazine. 1- (2, 6-dioxo) pyridin-2, 6-dione (278), 3- ((4- (5- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) but-3-yn-1-yl) oxy) azetidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (279), 5- (3- ((4- (5- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin-2-yl) cyclobutoxy) but-3-yn-1-yl) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (280), 5- (3- ((5- (1 r,3 r) -3H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin-2-yl) cyclobutoxy) pyridin-2-yl) indol-3-yn-1-yl-dione (280) 1-yl) oxy) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (281), 3- (5- ((5- (5- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) pent-4-yn-1-yl) oxy) azetidin-1-yl) -1-oxoisoindolin-2, 6-dione (282), 2- (2, 6-dioxopiperidin-3-yl) -5- ((1- (4- ((5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) but-3-yn-1-yl) azetidin-3-yl) 3- ((3-yl) isoindoline-2, 6-dione (282), 2- (3- ((1 r, 3-dioxo-3- ((3-yl) piperidine-3-dione) 3- ((3-yl) isoindoline-3- (283-1 r) -3- ((1 r) 3-yl) 5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclobutoxy) pyridin 2-yl) but-3-yn-1-yl-azetidin-3-yl) oxy) -1-oxoisoindolin-2-yl-piperidine-2, 6-dione (284), 5- (2, 2-difluoro-3- (4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclobutoxy) piperidin-1-yl) propoxy) -2- (2, 6-dioxopiperidin-3-yl) isoindolin-1, 3-dione (285), 2- ((1 r,3 r) -3- ((6- (3- ((2, 6-dioxopiperidin-3-yl) -1-oxo) oxy) propan-1-3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) piperidin-1-yl) propoxy) 2- (2, 6-dioxopiperidin-3-yl) isoindolin-1, 3-dione (285), 2- ((3- ((2, 6-dioxopiperidin-3-yl) 1-oxo) propan-1-oxo) 3-yl) pyrido-2-yl) amino - ((3- (5- ((1 r,3 r) -3- ((3-methyl-5- (5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) pyridin-2-yl) prop-2-ynyl) oxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (287); 3- (5- ((3- (5- ((1 r,3 r) -3- ((5- (4-chloro-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) prop-2-yn-1-yl) oxy) piperidin-2, 6-dione (288); 3- (5- ((3- ((1 r,3 r) -3- ((5- (4-fluoro-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) prop-2-ynyl) 2-oxo) 2-yl) indol-2-yl) 2-oxo-2-yl Diketones (289), 3- (5- ((3- (5- ((1 r,3 r) -3- ((5- (5- (difluoromethyl) -5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) propan-2-yn-1-yl) oxy) -1-oxoisoindolin-2, 6-dione (290), 2- (2, 6-dioxopiperidin-3-yl) -5- (2- ((3- (3- (((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) methyl) bicyclo [ 1.1.1.1.1 ] pent-1-yl) propan-2-yn-1-yl) oxy) ethoxy) isoindoline-1, 3-dione (291), 2- (2, 6-dioxopiperidin-3-yl) -5- (3- (((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin-2-yl) oxy) cyclobutoxy) ethoxy) isoindoline-1, 3-dione (291), 2- (3, 6-dioxopiperidin-3-yl) -5- ((3- (3-methyl) - ((3-1R) -3- ((3-1H-pyrido-7-yl) pyrido-yl) oxy) 2-yl) oxy ) Pyridin 2-yl) oxy) cyclobutyl) prop-2-yn-1-yl) oxy) ethoxy isoindoline-1, 3-dione (292), 3- (5- (4- ((3- (5- ((1 r,3 r) -3- ((5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclobutoxy) pyridin 2-yl) prop-2-yn-1-yl) oxy) piperidin-1-oxo isoindolin-2-yl) piperidine-2, 6-dione (293), 6- ((3- (5- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin 2-yl) ethoxy) -2- (2, 6-dioxopiperidin-3-yl) prop-1-yl) piperidin-2-yl) -1-2, 3- (3-dioxo-pyrrol-3-yl) piperidin-2-yl) piperidine-2, 6-dione (293), 6- ((3- (5H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin-2-yl) oxy) ethoxy - ((3- (((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) methyl) bicyclo [1.1. 1] pent-1-yl) methoxy) ethoxy-azetidin-1-yl-isoindoline-1, 3-dione (295), 2- (3- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) oxy) prop-1-yn-1-yl) -5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclobutoxy) isonicotinitrile (296), 2- (3- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-5-yl) oxy) prop-1-yn-1-yl) -5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy), 2- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxo-indol-5-yl) oxy) prop-1-yn-1-yl) -5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido-7-yl) pyridin-2-yl) oxy) cyclobutoxy) isonicotine (296) ) 3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclobutoxy) pyridin 2-yl) prop-2-yn-1-yl) oxy) ethoxy) isoindoline-1, 3-dione (298), 3- (5- ((3- (4-methyl-5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) pyridin 2-yl) prop-2-yn-1-yl) oxy) ethoxy) -1-oxoisoindolin-2, 6-dione (299), 3- (5- ((3- ((5- (1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) 4- (trifluoromethyl) pyridin 2-yl) prop-2-yn-1-yl) ethoxy) isoindoline-2, 6-dione (299) 1, 6-dioxopiperidin-2, 6-dione (300), 2- (2, 6-dioxopiperidin-3-yl) -5- (2- ((3- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) -4- (trifluoromethyl) pyridin-2-yl) prop-2-yn-1-yl) oxy) ethoxy) isoindoline-1, 3-dione (301), 6- (3- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) ethoxy) prop-1-yn-1-yl) -3- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) picoline nitrile (302), 6- (2, 6-dioxopiperidin-1-yl) ethoxy) isoindoline-1, 3-dione (302), 6- (2, 6-dioxopiperidin-3-yl) ethoxy) prop-1-yn-1-yl) 3- ((1 r,3 r) -3- ((5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) picoline nitrile (302) -yl) -3- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) picolininitrile (303), 2- (2, 6-dioxopiperidin-3-yl) -5- (2- ((3- (6-methyl-5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) prop-2-yn-1-yl) oxy) isoindoline-1, 3-dione (304), 3- (5- ((3- (6-methyl-5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) prop-2-oxy) 2-oxo) 2-1-oxo) 2-oxo) 2- (2, 305-dioxo-piperidone Pyridin-3-yl) -5- (2- ((3- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) -6- (trifluoromethyl) pyridin-2-yl) prop-2-yn-1-yl) oxy) ethoxy) isoindoline-1, 3-dione (306), 3- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) -6- (trifluoromethyl) pyridin-2-yn-1-yl) oxy) ethoxy) -1-oxoisoindolin-2, 6-dione (307), 2- (2, 6-dioxopiperidin-3-yl) -5- (2- ((2-methyl-4- (5 r) -3- ((5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) 6- (trifluoromethyl) prop-2-yn-1-yl) oxy) ethoxy 1- (2- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] pyridin-2-yl) cyclopropyloxy) ethoxy) -1-oxopiperidin-2-yl) but-3-yn-2-yloxy) ethoxy) -1-oxoisoindoline-2, 6-dione (309), 3- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] pyridin-7-yl) 2-yl) cyclopropyloxy) piperidin-2-yl) ethoxy), 3- (5- (1- ((5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) 2-yl) oxy) cyclopropyloxy) piperidin-2-yl) 2, 6-oxo-isoindoline-2, 6- ((2-oxo-2-yl) piperidine-2, 6-dione (309), 3- (2- (3 r,3 r) -3- ((5-methyl-5H-pyrido [4,3-b ] pyridin-7-yl) oxy) cyclopropyloxy) cyclopropylen-2-yl) piperidine-2-oxo-2-dione (309) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclobutoxy) pyridin 2-yl) ethynyl) cyclopropoxy ethoxy) isoindoline-1, 3-dione (311), 4- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) prop-1-yn-1-yl) -2- (4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) cyclobutoxy) piperidin-1-yl) benzonitrile (312), 4- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-5-yl) oxy) prop-1-yn-1-yl) -2- (4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxybutyloxy) piperidin-1-yl) benzonitrile (313), 3- ((2, 6-dioxopiperidin-3-yl) -1-yn-1-yl) oxy) prop-1-yn-1-yl) 3- ((5- (3- ((1 r, 3-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin 2-yl) oxy) piperidin-1-yl) benzonitrile (313), 3- ((3- ((3-methyl-3-2-dioxo-piperidin-3-yl) pyridin-3-yl) 2-yl) oxon-yl) oxol 7-yl) pyridin-2-yl) oxy) cyclobutoxy) piperidin-1-yl) phenyl) prop-2-yn-1-yl) oxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (314), 3- (5- ((3- (3- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) piperidin-1-yl) -4- (trifluoromethyl) phenyl) prop-2-yn-1-yl) oxy) 1-oxoisoindolin-2, 6-dione (315), 3- (5- ((3- (4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) piperidin-1-yl) -5- (trifluoromethyl) pyridin-2-yl) indol-2-yl) 2-oxo) 1-2-indolin-yl) isoindolin-2, 6-dione (315) 2, 6-dione (316), 6- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-5-yl) oxy) prop-1-yn-1-yl) -4- (4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) piperidin-1-yl) nicotinonitrile (317), 3- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) oxy) prop-1-yn-1-yl) -5- (4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) piperidin-1-yl) benzonitrile (318), 3- (2, 6-dioxopiperidin-3-yl) indol-1-yl) oxy) prop-1-yn-1-yl 1r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) piperidin-1-yl) benzonitrile (319), 3- (5- ((3- (3-methyl-5- (4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) piperidin-1-yl) phenyl) prop-2-yn-1-yl) oxy) -1-oxoisoindol-2-yl) piperidine-2, 6-dione (320), 3- (5- ((3- (3- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxybutyloxy) piperidin-1-yl) -5- (trifluoromethyl) phenyl) prop-2-yl) prop-1-oxy) piperidin-2-6-dione (320), 3- (3-yn-3-2-yl) 2-isoindol-1-yl) piperidine-3- (3-2-yl) 2-oxo) piperidine ((3- (4- (4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) piperidin-1-yl) -6- (trifluoromethyl) pyridin-2-yl) prop-2-yn-1-yl) oxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (322), 3- (5- ((3- (2- (4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) piperidin-1-yl) -6- (trifluoromethyl) pyridin-4-yl) prop-2-yn-1-yl) oxy) -1-oxoisoindol-2-yl piperidine-2, 6-dione (323), 2- (2, 6-dioxopiperidin-3-yl) -5- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) piperidin-1-yl) prop-2-yn-6-dione (323), 2- (2, 6-dioxopiperidin-3-yl) -5-methyl-4- (3-H-pyrido [ 4- (3-methyl) -3H-pyrido [ 4-yl ] pyridin-2-yl ] pyrido [ 3-yl ] 2-yl ] piperidine-2 (b) indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) piperidin-1-yl) phenyl) but-3-yn-2-yl) oxy) isoindoline-1, 3-dione (324), 3- (5- ((2-methyl-4- (3- ((5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) piperidin-1-yl) phenyl) but-3-yn-2-yl) piperidin-2, 6-dione (325), 3- (5- ((2-methyl-4- (4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) piperidin-1-yl) but-3-2-yl) piperidin-2- (5-methyl-4- ((1-yl) oxy) pyridin-2-yl) piperidin-3-2, 6-dione (325), 3- (5- ((2-methyl-4- (4-r, 3-b) indol-7-yl) pyridin-2-yl) 2-oxo) piperidin-3-2-yl) 2-oxo-1-dione (326) ((1, 1-difluoro-3- (4- (4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) piperidin-1-yl) pyridin-2-yl) prop-2-yn-1-yl) Oxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (328), 6- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) oxy) -3-methylbutan-1-yl) -4- (4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) piperidin-1-yl) pyrimidin-2-yl) but-3-yn-2-yloxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (328), 6- (3- ((2, 6-dioxopiperidin-3-yl) oxy) -3-methylbutan-1-yl) -4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) cyclobutoxy) piperidin-1-yl) piperidine-2, and 3- ((2- (3-dioxo) -2-oxo) -1-piperidyl) piperidine-2, 6-dione (328) Indolin-5-yl) oxy) ethoxy) -3-methylbut-1-yn-1-yl) -5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) isonicotinic acid (330).
Where applicable, the present specification includes compositions comprising pharmaceutically acceptable salts, particularly acid or base addition salts of the compounds of the present disclosure.
Where applicable, the term "pharmaceutically acceptable salt" is used throughout the specification to describe salt forms of one or more compounds described herein, which are used to increase the solubility of the compound in gastric juice of the gastrointestinal tract of a patient, so as to promote dissolution and bioavailability of the compound. Where applicable, pharmaceutically acceptable salts include salts derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium, magnesium and ammonium salts, and numerous other acids and bases well known in the pharmaceutical arts. Sodium and potassium salts are particularly preferred as the neutralized salts of the phosphates according to the present disclosure.
The acids used to prepare the pharmaceutically acceptable acid addition salts of the above-described base compounds useful in the present disclosure are those acids that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate [ i.e., 1' -methylene-bis- (2-hydroxy-3-naphthoic acid) ] salts, and the like.
Pharmaceutically acceptable base addition salts may also be used to produce pharmaceutically acceptable salt forms of the compounds or derivatives according to the present disclosure. Chemical bases that are acidic in nature that can be used as reagents for preparing pharmaceutically acceptable basic salts of the compounds herein are those that form non-toxic basic salts with such compounds. Such non-toxic basic salts include, but are not limited to, those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium, zinc and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine- (meglumine), as well as other basic salts of lower alkanolammonium and pharmaceutically acceptable organic amines, and the like.
Composition:
In another aspect, the present specification provides compositions comprising a compound as described herein, including salts thereof, and a pharmaceutically acceptable carrier. In certain embodiments, the composition is a therapeutic or pharmaceutical composition comprising an effective amount of a compound as described herein and a pharmaceutically acceptable carrier.
The amount of compound in the pharmaceutical compositions of the present disclosure that can be combined with a carrier material to produce a single dosage form will vary depending upon the host and disease being treated, the particular mode of administration. Generally, depending on the potency of the agent, an amount of active ingredient of 0.1mg/kg to 1000mg/kg body weight/day is administered. Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the LD50/ED50 ratio. Compounds that exhibit large therapeutic indices are preferred. While compounds exhibiting toxic side effects may be used, care should be taken to design delivery systems that target such compounds to the affected tissue site in order to minimize potential damage to uninfected cells and thereby reduce side effects. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds is preferably within a range of circulating concentrations that includes the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound used in the methods of the present disclosure, a therapeutically effective dose may be estimated initially from cell culture assays. Dosages may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of test compound that achieves half-maximal inhibition of symptoms) as determined in cell culture. Such information may be used to more accurately determine useful doses in humans. For example, the level in plasma may be measured by high performance liquid chromatography.
The compositions of the present disclosure may be formulated in conventional manner using one or more pharmaceutically acceptable carriers and may also be administered in controlled release formulations. Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as prolamin sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin.
In any aspect or embodiment described herein, the PTM, ULM, or both have an affinity (IC 50) for their respective target protein of less than about 500μM、450μM、400μM、350μM、300μM、250μM、200μM、150μM,100μM、50μM、10μM、0.10μM、0.01μM,0.001μM、0.1nM、0.01nM、0.001nM or less. In view of this disclosure, the determination of IC 50 may be performed using methods well known to those skilled in the art.
In any aspect or embodiment, the compounds as described herein achieve ubiquitination of a target protein at a level or amount sufficient to achieve or induce degradation of the target protein.
The active compound is included in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount for the desired indication without causing serious toxic effects in the patient being treated. Preferred dosages of the active compound for all of the conditions mentioned herein are in the range of about 10ng/kg to 300mg/kg, preferably 0.1 to 100 mg/kg/day, more typically 0.5 to about 25 mg/kg of body weight of the recipient/patient/day. Typical topical dosages range from 0.01 to 5% wt/wt in a suitable carrier.
The compound is conveniently administered in any suitable unit dosage form including, but not limited to, unit dosage forms containing less than 1mg, 1mg to 3000mg, preferably 5 to 500mg of active ingredient per unit dosage form. An oral dosage of about 25-250mg is often convenient.
The active ingredient is preferably administered to achieve a peak plasma concentration of the active compound of about 0.00001 to 30mM, preferably about 0.1 to 30. Mu.M. This can be achieved, for example, by intravenous injection of a solution or formulation of the active ingredient, optionally in saline or aqueous medium, or as a bolus injection of the active ingredient. Oral administration is also suitable for producing effective plasma concentrations of the active agent.
The concentration of the active compound in the pharmaceutical composition will depend on the absorption, distribution, inactivation, and excretion rates of the drug, as well as other factors known to those of skill in the art. It should be noted that the dosage value will also vary with the severity of the condition to be alleviated. It will also be appreciated that for any particular subject, the particular dosage regimen should be adjusted over time according to the individual needs and the professional judgment of the individual administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions. The active ingredient may be administered at one time or may be divided into a number of smaller doses and administered at different time intervals.
If administered intravenously, the preferred carrier is physiological saline or Phosphate Buffered Saline (PBS).
In one embodiment, the active compound is prepared with a carrier that will protect the compound from rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid may be used. Methods for preparing such formulations will be apparent to those skilled in the art.
The liposome suspension may also be a pharmaceutically acceptable carrier. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811 (which is incorporated herein by reference in its entirety). For example, liposome formulations can be prepared by dissolving the appropriate lipids (e.g., stearoyl phosphatidylethanolamine, stearoyl phosphatidylcholine, arachido phosphatidylcholine, and cholesterol) in an organic solvent, and then evaporating the organic solvent, leaving a thin film of dried lipid on the surface of the container. An aqueous solution of the active compound is then introduced into the container. The vessel is then rotated by hand to release the lipid material from the sides of the vessel and disperse the lipid aggregates, thereby forming a liposome suspension.
Mode of administration
In any aspect or embodiment described herein, the therapeutic composition comprising the compounds described herein may be in any suitable dosage form configured for delivery by any suitable route. For example, the compounds may be administered by any suitable route, such as orally, parenterally, intravenously, intradermally, subcutaneously, or topically (including transdermally, in liquid, cream, gel, or solid form), rectally, nasally, bucally, vaginally, or via an implanted reservoir, or by aerosol form.
As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally, or intravenously.
The compounds as described herein may be administered in single or divided doses by oral, parenteral or topical routes. The administration of the active compound can range from continuous (intravenous instillation) to several times daily oral administration (e.g., q.i.d.), and can include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which can include penetration enhancers), buccal, sublingual, and suppository administration, as well as other routes of administration. Enteric coated oral tablets may also be used to enhance the bioavailability of compounds from the oral route of administration. The most effective dosage form depends on the pharmacokinetics of the particular agent selected and the severity of the disease in the patient.
Compound administration as a spray, mist or aerosol for intranasal, intratracheal or pulmonary administration may also be used. The compounds as described herein may be administered in immediate release, intermediate release or sustained or controlled release form. Sustained or controlled release forms are preferably administered orally, but also suppositories and transdermal or other topical forms. Intramuscular injection in the form of liposomes can also be used to control or maintain the release of the compound at the injection site.
The sterile injectable form of the compositions as described herein may be an aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as ph.
The pharmaceutical compositions as described herein may be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, common carriers include lactose and corn starch. A lubricant, such as magnesium stearate, is also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is desired for oral use, the active ingredient is mixed with emulsifying and suspending agents. If desired, certain sweeteners, flavoring agents or coloring agents may also be added. Oral compositions generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound or prodrug derivative thereof may be mixed with excipients and used in the form of tablets, troches or capsules. Pharmaceutically compatible binders and/or adjuvant materials are included as part of the composition.
Tablets, pills, capsules, troches and the like may contain any of a variety of ingredients or compounds of similar nature such as binders such as microcrystalline cellulose, gum tragacanth or gelatin, excipients such as starch or lactose, dispersants such as alginic acid, primogel or corn starch, lubricants such as magnesium stearate or Sterotes, glidants such as colloidal silicon dioxide, sweeteners such as sucrose or saccharin, or flavoring agents such as peppermint, methyl salicylate or orange flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the type described above, a liquid carrier such as a fatty oil. In addition, the dosage unit form may contain various other substances that modify the physical form of the dosage unit, such as sugar coatings, shellac, or enteric solvents.
The active compound or pharmaceutically acceptable salt thereof can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum, and the like. Syrups may contain, in addition to the active compounds, sucrose as a sweetener, together with certain preservatives, dyes and colorants and flavors.
Alternatively, the pharmaceutical compositions as described herein may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
The pharmaceutical compositions of the present disclosure may also be administered topically. For each of these regions or organs, a suitable topical formulation is readily prepared. Topical administration to the lower intestinal tract may be achieved in rectal suppository formulations (see above) or in suitable enema formulations. Topically acceptable transdermal patches may also be used. For topical application, the pharmaceutical compositions may be formulated as a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical application of compounds of the present disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water. In certain preferred aspects of the present disclosure, compounds may be coated onto a stent to be surgically implanted in a patient in order to inhibit or reduce the likelihood of the stent becoming blocked in the patient.
Alternatively, the pharmaceutical compositions may be formulated as a suitable lotion or cream containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetostearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
For ophthalmic use, the pharmaceutical composition may be formulated as a micronized suspension in isotonic, pH adjusted sterile saline, or preferably, as a solution in isotonic, pH adjusted sterile saline, with or without a preservative such as benzalkonium chloride. Alternatively, for ocular use, the pharmaceutical composition may be formulated as an ointment such as petrolatum.
The pharmaceutical compositions of the present disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
Solutions or suspensions for parenteral, intradermal, subcutaneous or topical administration may include sterile diluents such as water for injection, saline solutions, fixed oils, polyethylene glycols, glycerol, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol or methyl parahydroxybenzoate, antioxidants such as ascorbic acid or sodium bisulfite, chelating agents such as ethylenediamine tetraacetic acid, buffers such as acetates, citrates or phosphates and agents for modulating tonicity such as sodium chloride or dextrose. Parenteral formulations may be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plastic.
It will also be appreciated that the specific dosage and treatment regimen for any particular patient will depend upon a variety of factors including the activity of the particular compound employed, the age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, as well as the judgment of the treating physician and the severity of the particular disease or condition being treated.
A patient or subject in need of treatment with a compound as described herein may be treated by administering to the patient (subject) an effective amount of the compound, including pharmaceutically acceptable salts, solvates, or polymorphs thereof, alone or in combination with other known agents, optionally in a pharmaceutically acceptable carrier or diluent.
Co-administration
Disease states of conditions that may be treated using compounds or compositions according to the present description include, but are not limited to, for example, cancer (e.g., prostate cancer) and kennedy's disease. In certain embodiments, the therapeutic or pharmaceutical composition comprises an effective amount of an additional biologically or bioactive agent, e.g., a co-administered agent effective for the treatment of cancer.
The term "co-administration" or "combination therapy" shall mean that at least two compounds or compositions are administered to a patient simultaneously, such that an effective amount or concentration of each of the two or more compounds can be found in the patient at a given point in time. Although compounds according to the present disclosure may be co-administered to a patient at the same time, the term includes administration of two or more agents at the same time or at different times, provided that the effective concentration of all co-administered compounds or compositions is found in the subject at a given time. In certain preferred aspects of the present disclosure, one or more of the compounds described herein are co-administered in combination with at least one additional bioactive agent, including, inter alia, anticancer agents. In certain preferred aspects of the present disclosure, co-administration of the compounds results in synergistic treatments, including anti-cancer therapies.
In another aspect, the present specification provides a composition comprising an effective amount of two or more compounds PROTAC as described herein and a pharmaceutically acceptable carrier. In certain embodiments, the composition further comprises an effective or synergistic amount of another bioactive agent that is not a PROTAC compound.
A pharmaceutical composition represents a further aspect of the present disclosure, comprising a combination of an effective amount of at least one bifunctional compound according to the present disclosure and one or more compounds described further elsewhere herein, in combination with a pharmaceutically effective amount of a carrier, additive or excipient.
The term "bioactive agent" is used to describe an agent other than the PROTAC compounds described herein that is used in combination with the compounds herein as a bioactive agent to help achieve the desired therapy, inhibition, and/or prevention/prophylaxis for its use of the compounds herein. Preferred bioactive agents for use herein include those agents that aid in achieving the desired therapy, such as P-gp inhibitors or agents that have similar pharmacological activity to that for which the compounds herein are used or administered, and include, for example, anti-neurodegenerative agents.
The term "P-gp" was used to describe the "permeant glycoprotein" or P-glycoprotein (ABCB 1) found in rodent cells in 1976. The presence of "endogenous or physiological" P-gp is a potential problem in achieving targeted exposure with therapeutic agents. P-gp is expressed at barrier tissues (e.g., the blood brain barrier) and secretory/absorptive tissues (e.g., the gastrointestinal tract) against the refuge site (Cordon-Cardo et al, 1989, 1990). The proteins act as cellular defenses and affect the overall pharmacokinetic profile of many drugs by actively pumping them out of the intracellular environment (efflux), thereby reducing drug penetration of the barrier tissue. In particular, P-gp efflux reduces drug permeability across the gastrointestinal tract membrane and can result in reduced systemic exposure of the drug. P-gp efflux may also reduce drug entry across the blood brain barrier. P-gp inhibitors may contribute indirectly to efficacy by increasing PROTAC exposure, particularly CNS exposure
The term "additional anti-neurodegenerative agent" is used to describe an anti-neurodegenerative agent that may be combined with PROTAC compounds according to this specification to treat a neurodegenerative disease.
In certain embodiments PROTAC is used in conjunction with a P-gp inhibitor.
In certain further embodiments, the P-gp inhibitor is selected from, but is not limited to, amiodarone, azithromycin, captopril, clarithromycin, cyclosporin, piperine, quercetin, quinidine, quinine, reserpine, ritonavir, tarquidambar, irinotecan, and verapamil.
Therapeutic method
In another aspect, the present disclosure provides a method of modulating protein ubiquitination and degradation in a subject (e.g., a cell, tissue, mammal, or human patient), comprising administering to the subject an effective amount of a PROTAC compound as described herein, or a composition comprising an effective amount thereof, wherein the compound or composition comprising the same is effective to modulate protein ubiquitination and protein degradation in the subject. In certain embodiments, the protein is a Tau protein.
In certain embodiments, the present description provides methods for modulating the protein activity of a Tau protein by degrading a Tau aggregate in a patient in need thereof, comprising administering to the patient an amount of a compound as described herein.
In yet further embodiments, the present specification provides a method of treating a disease state or condition in a patient, wherein deregulated protein activity (Tau aggregation and accumulation) is responsible for the disease state or condition, the method comprising administering to the patient an effective amount of a compound as described herein, so as to modulate the protein activity in the patient. In certain embodiments, the protein is Tau.
As used herein, the terms "treatment", "treatment" and the like refer to any action that provides a benefit to a patient for whom a compound herein may be administered, including treatment of any disease state or condition modulated by the protein to which the compound herein binds. Disease states or conditions that may be treated using compounds according to the present disclosure, including neurological and neurodegenerative diseases, are set forth above.
In another aspect, the present disclosure provides a method of modulating Tau protein ubiquitination and degradation in a subject (e.g., a cell, tissue, mammal, or human patient), the method comprising administering to the subject an effective amount of a compound as described herein or a composition comprising an effective amount of a compound as described herein, wherein the compound or composition comprising the same is effective to modulate Tau protein ubiquitination and protein degradation in the subject.
In another aspect, the present disclosure provides a method of treating or ameliorating a symptom of a disease associated with Tau accumulation or aggregation in a subject (e.g., a cell, tissue, mammal, or human patient), the method comprising administering to a subject in need thereof an effective amount of a compound as described herein or a composition comprising an effective amount thereof, wherein the compound or composition comprising the same is effective to treat or ameliorate a symptom of a disease associated with Tau aggregation in a subject.
In certain embodiments, the disease or disorder is a neurological disorder including, but not limited to, loss of zona pellucida, acquired epileptiform aphasia, acute disseminated encephalomyelitis, ADHD, addison's pupil, addison's syndrome, adrenoleukodystrophy, callose dysplasia, agnosia, alkadi syndrome, AIDS-neurological complications, alexander disease, alter's disease, alternating hemiplegia, alzheimer's disease, amyotrophic lateral sclerosis, cerebral deformity, aneurysms, angel's syndrome, hemangiomatosis, hypoxia, aphasia, misuse, arachnoid cyst, arachnoiditis, alzhi deformity, arteriovenous deformity, The symptoms include Alzheimer's syndrome, ataxia, telangiectasia, ataxia and cerebellar/spinal cerebellar degeneration, attention deficit hyperactivity disorder, autism, autonomic dysfunction, back pain, papanic syndrome, barbit's disease, beckian myotonic, behcet's disease, bell's palsy, benign essential blepharospasm, benign focal muscular atrophy, benign intracranial hypertension, berry's-Luo Ershi syndrome, binder's disease, blepharospasm, bu-Su Ershi syndrome, brachial plexus injuries, bradbury-Eggleston syndrome, brain and spinal tumors, cerebral aneurysms, brain injuries, brown-Szewal syndrome, Bulbar amyotrophy, kanwana disease, carpal tunnel syndrome causalgia, spongiform tumor, cavernous hemangioma, spongiform vascular malformation, central cervical syndrome, central chordae syndrome, central pain syndrome, cranial disorders, cerebellar degeneration, cerebellar hypoplasia, cerebral aneurysm, cerebral arteriosclerosis, brain atrophy, brain beriberi, cerebral giant, cerebral anoxia, cerebral paralysis, brain-eye-face-bone syndrome, summer-horse-figure three disease, chiari malformation, chorea acanthocytosis, chronic Inflammatory Demyelinating Polyneuropathy (CIDP), chronic erectile intolerance, chronic pain type II cocaine syndrome, Ke-Letwo syndrome, COFS, cavitary brain, comatose and persistent plant states, complex regional pain syndrome, congenital facial paralysis, congenital muscle weakness, congenital myopathy, congenital spongiform vessels, deformity, corticobasal degeneration, craniofacial arteritis, craniospasm premature closure, creutzfeldt-Jakob disease, cumulative trauma disorder, cushing's syndrome, giant cell inclusion body disease, cytomegalovirus infection, oculopathy syndrome, dan-Wo Ershi syndrome, androson's disease, demoxidec syndrome, deep brain stimulation of Parkinson's disease, dejerine-Klumpke paralysis, dementia-multiple cerebral infarction, dementia-semanteme, and the like, Dementia-subcortical, lewy body dementia, dentate nucleus cerebellar ataxia, dentate nucleus erythronuclear atrophy, dermatomyositis, developmental dyskinesia, devickers syndrome, diabetic neuropathy, diffuse sclerosis, familial autonomic nerve abnormalities, dysprosia, dysreading, dysphagia, dyskinesia, cerebellar dyssynergia, myoclonus, progressive cerebellar dyssynergia, dystonia, early stage infant epilepsy, encephalopathy, jetlag syndrome, comatose encephalitis, brain bulge, encephalopathy, trigeminal angiomatosis, epilepsy, erb-Duchenne and Dejerine-Klumpke paralysis, european Bobber's paralysis, Fabry disease, french syndrome, syncope, familial autonomic dysfunction, familial hemangioma, familial idiopathic basal ganglia calcification, familial periodic paralysis, familial spastic paralysis, febrile convulsion, fisher syndrome, flaccid infant syndrome, friedel-crafts ataxia, frontotemporal dementia, gaucher's disease, gray's disease, grignard Shi Xiesan disease, giant cell arteritis, giant cell inclusion body disease, globus-cell leukodystrophy, glossopharyngalgia, grignard-Barbie syndrome, hash-Sjogren's disease, head injury, headache, persistent migraine, hemifacial spasm, hemiplegia Alterans, hereditary neuropathy, Hereditary spastic paraplegia, hereditary ataxia polyneuritis, shingles, ping Shan syndrome, hodgher's syndrome, forebrain crazy deformity, HTLV-1 related myelopathy, huntington's disease, water retention cerebral deformity, hydrocephalus-normal pressure, hydrocephalus, hyperkinesia, hypercortisolism, hypersomnia, hypotonia-infant, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, pigment incontinence, hypotonia of infant, infantile nerve axonal dystrophy, infant phytanic acid storage disease, infant Lei Fusu m disease, infantile cramps, inflammatory myopathy, Occipital split cerebral dew deformity, intestinal lipodystrophy, intracranial cysts, intracranial hypertension, isaacs syndrome, zhu Bate syndrome, kennel-Sachs syndrome, kennedy's disease, kingbriner's syndrome, kernel-Living syndrome, kernel-Fei Ershi syndrome, kernel-Techner's syndrome (KTS), kernel-Buddy's syndrome, kosakoff forgetting syndrome, kerabe disease, cookawer's disease, kuru, landau-Airy's muscle weakness syndrome, landau-Klefner syndrome, lateral femoral, cutaneous nerve entrapment, bulbar lateral syndrome, learning disorders, lei's disease, lei-Goos syndrome, lei-Nardy's syndrome, Leukodystrophy, levine-CRITCHLEY syndrome, lewy body dementia, lipid storage disorder, cerebral palsy, atresia syndrome, gray's disease, lupus-neurology, sequelae, lyme disease-neurological complications, equine-Johnson's disease, megabrain, mania, megabrain, michelia-Luo Ershi syndrome, meningitis and encephalitis, mentha's disease, paresthesia femoral pain, metachromatic, leukodystrophy, microcephaly, migraine, millefre's syndrome, small stroke, mitochondrial myopathy, morbites syndrome, single limb atrophy, motor neuron disease, smogopathy, mucolipidosis, Mucopolysaccharidoses, multifocal motor neuropathy, multi-infarct dementia, multiple sclerosis, multiple system atrophy with orthostatic hypotension, muscular dystrophy, muscle weakness-congenital, myasthenia gravis, demyelinating diffuse sclerosis, infant myoclonus encephalopathy, myoclonus, myopathy-congenital, myopathy-thyrotoxicosis, myotonia, congenital myotonia, narcolepsy, acanthocytosis, neurodegenerative disorders with brain iron deposition, neurofibromatosis, nerve blocker malignancy, neurological complications of AIDS, neurological complications of lyme disease, neurological consequences of cytomegalovirus infection, Neurological manifestations of pompe disease, neurological sequelae of lupus, neuromyelitis optica, neuromyotonia, neuronal ceroid, lipofuscinosis, neuronal migration disorders, neuropathy-hereditary, neurosarcoidosis, neurotoxicity, moles cavernosum, niemann-pick disease, normal pressure hydrocephalus, occipital neuralgia, obesity, recessive spinal neural tube insufficiency sequences, dada syndrome, olivopontocerebellar atrophy, strabismus-clonus myoclonus, orthostatic hypotension, O' Sullivan-McLeod syndrome, overuse syndrome, pain-chronic, pain, pantothenate kinase-related neurodegeneration, Paraneoplastic syndrome, paresthesia, parkinson's disease, paroxysmal chorea athetosis, paroxysmal migraine, parry-Romberg, pet-Mei-two's disease, pena Shokeir II syndrome, nerve bundle cyst, periodic paralysis, peripheral neuropathy, periventricular leukomalacia, persistent plant status, pervasive developmental disorder, phytanic acid storage disease, pick's disease, neuromarking, piriform muscle syndrome, pituitary tumor, polymyositis, pompe disease, pornoglos, postherpetic neuralgia, post-infection encephalomyelitis, post-poliomyelitis syndrome, orthostatic hypotension, Tachycardia syndrome, postural tachycardia syndrome, primary Dentatum atrophy, primary lateral sclerosis, primary progressive aphasia, prion diseases, progressive hemifacial atrophy, progressive motor ataxia, progressive multifocal, leukoencephalopathy, progressive sclerosing gray matter dystrophy, progressive supranuclear, paralysis, face-unknown, pseudoencephaloma, lambdazin hunter syndrome I (previously known), lambdazin hunter syndrome II (previously known), rasmussen encephalitis, reflex sympathetic dystrophy syndrome, lei Fusu m disease, lei Fusu m disease-infancy, repetitive movement disorder, Repetitive stress injury, restless leg syndrome, retrovirus-associated spinal cord disease, rate's syndrome, rayleigh-Dai Ershi syndrome, sacral nerve root cyst, saint Vitex's chorea, salivary gland disease, mordeHough's disease, shebrew's disease, cerebral fissure, saint Begonia disease, epilepsy, semantic dementia, dysplasia of the visual-septa type, infant swing syndrome, SHINGLES SHY-Drager syndrome, sjogren's syndrome, sleep apnea, comatose, sotos syndrome, spasticity, spinal column fissure, spinal infarction, spinal cord injury, spinal cord tumor, spinal muscular atrophy, spinal cerebellar atrophy, Spinocerebellar, degenerative, sri-Otts syndrome, stiff person syndrome, striatal degeneration, stroke, sri-Weber syndrome, subacute sclerotic encephalitis, subcortical arteriosclerotic encephalopathy, SUNCT headache dysphagia, west Duham chorea, syncope, syphilitic myelosclerosis, syringohol's disease, systemic lupus erythematosus, phthisis tardive dyskinesia, tarlov cyst, tarlov-Satwo's disease, temporal arteritis, spinal cord embolic syndrome, thomsen's myotonic, chest outlet syndrome, thyrotoxicosis, trigeminal neuralgia, todder paralysis, tourette syndrome, transient ischemic attacks, transmissible spongiform encephalopathy, transverse myelitis, traumatic brain injury, tremor, trigeminal neuralgia, tropical spastic lower limb paralysis, nodular sclerosis, vascular erectile tumors, vasculitis including temporal arteritis, embopogon disease, hill-Lin's disease (VHL), feng Leike Lin Huozeng's disease, walen Bei Geshi syndrome, wer-Huo Ershi disease, west syndrome, whiplash syndrome, hupler's disease, williams syndrome, wilson's disease, X-linked spinal bulbar atrophy or Zellweger syndrome.
In certain embodiments, the disease or condition is at least one of Huntington's disease, muscular dystrophy, parkinson's disease, alzheimer's disease, barter's disease, spinal cord and brain injuries, epilepsy, brain tumors, meningitis, autoimmune diseases such as multiple sclerosis, neurofibromatosis, depression, amyotrophic lateral sclerosis, arteriovenous malformations, cerebral aneurysms, dural arteriovenous fistulae, headaches, memory disorders, peripheral neuropathy, post-herpetic neuralgia, spinal cord tumors, and strokes.
In certain embodiments, the disease or disorder is alzheimer's disease.
In another aspect, the present disclosure provides a method of treating or ameliorating a symptom of a disease associated with Tau accumulation or aggregation in a subject (e.g., a cell, tissue, mammal, or human patient), the method comprising administering to a subject in need thereof an effective amount of a compound as described herein or a composition comprising an effective amount thereof and an effective or synergistic amount of another bioactive agent, wherein the composition comprising the same is effective to treat or ameliorate the symptom of the disease associated with Tau accumulation or aggregation in the subject by Tau degradation/inhibition.
In certain embodiments, the disease to be treated is a neurological disorder. In a preferred embodiment, the subject is a human.
In certain further embodiments, the additional bioactive agent is an anti-neurodegenerative agent.
In an alternative aspect, the present disclosure relates to a method for treating a disease state by degrading a protein or polypeptide by which the disease state or condition is modulated, comprising administering to the patient or subject an effective amount of at least one compound as described above, optionally in combination with an additional bioactive agent. Methods according to the present disclosure may be used to treat a variety of neurological states or conditions due to the administration of an effective amount of at least one compound described herein.
In another aspect, the present disclosure provides methods for identifying the effects of degradation of a protein of interest in a biological system using compounds according to the present disclosure.
Kit for detecting a substance in a sample
In another aspect, the present description provides a kit comprising a compound or composition as described herein. Kits may be promoted, distributed, or sold as a unit for performing the methods of the present disclosure. In addition, the kits of the present disclosure may preferably contain instructions describing suitable uses. Such kits may be conveniently used, for example, in a clinical setting, to treat patients suffering from a neurological disorder.
Examples
PROTAC compounds of the present disclosure are effective in Tau degradation. Exemplary compounds are presented in tables 1 and 2, wherein in vitro data for some selected compounds in tables 2 and 3 show degradation of tau protein. In vivo studies showing tau protein degradation are shown in figure 1.
General method of chemical Synthesis
The synthesis of the claimed chimeric compounds can be carried out according to the general synthetic procedures known in the literature. The synthetic routes shown in schemes in this disclosure are described as one of the methods that can be used to obtain the desired compounds. Other methods may also be useful to those skilled in the art of synthesis. The ULMs and PTMs described in the schemes represent only one of many ULMs and PTMs in this patent application.
LC-MS method for purity analysis (quality control)
LCMS method:
Instrument AGILENT INFINITY 1260 LC;Agilent 6230 TOF Mass Spectrometry
Analysis was performed on Poroshell EC C18 column (50 mm. Times.3.0 mm inner diameter 2.7 μm packed diameter) at 45 ℃.
The solvents used were:
A=0.1% v/v formic acid in water.
B=0.1% v/v formic acid in acetonitrile.
The gradient used is as follows:
UV detection is an average signal at wavelengths of 210nm to 350nm and mass spectra were recorded on a mass spectrometer using positive mode electrospray ionization.
Abbreviations:
ACN acetonitrile
Boc 2 O di-tert-butyl dicarbonate
DCM: dichloromethane.
DIPEA N, N-diisopropylethylamine
DMA N, N-dimethylacetamide
DMF N, N-dimethylformamide
EA ethyl acetate
HATU 2- (7-aza-1H-benzotriazol-1-yl) -1, 3-tetramethyluronium hexafluorophosphate
HPLC high performance liquid chromatography
LC-MS liquid chromatography-Mass Spectrometry
Min Min
MTBE methyl tert-butyl ether
PE Petroleum ether
RT room temperature
SPB sodium perborate
TBu-t-butyl
TBACl tetrabutylammonium chloride
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography
TMS trimethylsilyl group
T R retention time
TsCl p-toluenesulfonyl chloride
Intermediate product of ubiquitin E3 ligase targeting moiety (ULM) and Protein Targeting Moiety (PTM)
Intermediate 1 (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethylbutyryl ] -4-hydroxy-N- [ [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] methyl ] pyrrolidine-2-carboxamide hydrochloride (ULM-1)
Step 1 preparation of 4- (4-methyl-1, 3-thiazol-5-yl) benzonitrile
To a stirred solution of 4-bromobenzonitrile (20 g,109.88 mmol) in DMA (250 mL) at room temperature under nitrogen atmosphere was added 4-methyl-1, 3-thiazole (21.88 g,220.67 mmol), palladium (II) acetate (743 mg,3.31 mmol) and potassium acetate (21.66 g,220.71 mmol). The resulting mixture was heated to 150 ℃ and stirred at that temperature for 5 hours, at which point LC-MS indicated the reaction was complete. The mixture was cooled to room temperature, diluted with 1L of water, and extracted with ethyl acetate (300 ml x 3). The organic layers were combined, washed with brine (200 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a crude residue, which was purified by flash column chromatography (eluent: ethyl acetate/petroleum ether, v: v=1:5) to give the title compound as a white solid (yield: 91%).
Step 2 preparation of [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] methylamine
To a stirred solution of 4- (4-methyl-1, 3-thiazol-5-yl) benzonitrile (35 g,174.77 mmol) in tetrahydrofuran (1000 mL) under nitrogen atmosphere at 0℃over 10 minutes was added LiAlH 4 (20 g,526.32 mmol) in portions. The resulting mixture was then stirred at 60 ℃ for 3 hours, at which point LC-MS indicated the reaction was complete. The mixture was cooled to 0 ℃ and then quenched by the addition of water (20 mL, slow addition), aqueous NaOH (15%, 20 mL) and water (60 mL). The resulting mixture was then extracted with ethyl acetate (300 ml x 2). The organic layers were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a crude residue, which was purified by flash column chromatography (eluent: dichloromethane/methanol (v: v=10:1)) to give the title compound as a yellow oil (yield: 56%).
Step 3 preparation of tert-butyl (2S, 4R) -4-hydroxy-2- ([ [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] methyl ] carbamoyl) pyrrolidine-1-carboxylic acid ester
To a stirred solution of (2S, 4R) -1- [ (tert-butoxy) carbonyl ] -4-hydroxypyrrolidine-2-carboxylic acid (2.7 g,11.68 mmol) in N, N-dimethylformamide (20 mL) was added DIPEA (2.52 g,19.50 mmol), HATU (4.47 g,11.76 mmol) and [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] methylamine (2 g,9.79 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight at which time LC-MS indicated the reaction was complete. The reaction mixture was diluted with 20mL of water and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a crude residue, which was purified by flash column chromatography (eluent: dichloromethane/methanol (v: v=20:1)) to give the title compound as a yellow solid (yield: 56%).
Step 4 preparation of (2S, 4R) -4-hydroxy-N- [ [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] methyl ] pyrrolidine-2-carboxamide hydrochloride
To a 1L round bottom flask containing a dioxane solution of tert-butyl (2 s,4 r) -4-hydroxy-2- ([ [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] methyl ] carbamoyl) pyrrolidine-1-carboxylate (45 g,107.78 mmol) was added a dioxane solution of hydrogen chloride (4 n,300 ml). The resulting solution was stirred at room temperature for 2 hours. The solid was collected by filtration to give the title product as a yellow solid (yield: 98%).
Step 5 preparation of tert-butyl N- [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- ([ [4- (4-methyl-1, 3-thiazol-5-yl) ] phenyl ] methyl ] carbamoyl) pyrrolidin-1-yl ] -3, 3-dimethyl-1-oxobutan-2-yl ] carbamate
To a stirred solution of (2S) -2- { [ (tert-butoxy) carbonyl ] amino } -3, 3-dimethylbutyric acid (15.7 g,68.0 mmol) in N, N-dimethylformamide (500 mL) was added DIPEA (29.2 g,225.9 mmol), HATU (25.9 g,68.1 mmol) and (2S, 4R) -4-hydroxy-N- { [4- (4-methyl-1, 3-thiazol-5-yl) -phenyl ] methyl } pyrrolidine-2-carboxamide hydrochloride (20.0 g,56.5 mmol) at room temperature.
The resulting solution was stirred at room temperature for 16 hours and LC-MS indicated the formation of the desired product. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The organic layers were combined, washed with saturated aqueous solution of sodium chloride (50 ml x 2), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a crude residue, which was purified by flash chromatography on silica gel (eluent: ethyl acetate/petroleum ether (v: v=2:1)) to give the title compound as a yellow solid (yield: 51%).
Step 6 Synthesis of (2S, 4R) -1- [ (2S) -2-amino-3, 3-dimethylbutyryl ] -4-hydroxy-N- [ [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] methyl ] pyrrolidine-2-carboxamide hydrochloride (ULM-1)
To a stirred solution of tert-butyl N- [ (2S) -1- [ (2S, 4 r) -4-hydroxy-2- ([ [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] methyl ] carbamoyl) pyrrolidin-1-yl ] -3, 3-dimethyl-1-oxobutan-2-yl ] carbamate (12 g,22.61 mmol) in dioxane (20 mL) at room temperature was added a solution of hydrogen chloride in dioxane (4N, 80 mL). The resulting solution was stirred at room temperature for 2 hours, at which time LC-MS indicated the reaction was complete. The precipitated solid was collected by filtration to give the title product as a yellow solid (yield: 48%).
D: 48%) as a yellow solid.
1HNMR(400MHz,CD3OD):δ9.84-9.82(s,1H),7.58-7.54(m,4H),4.71-4.41(m,4H),4.13-4.08(m,1H),3.86-3.71(m,2H),3.36(s,1H),2.60-2.58(s,3H),2.35-2.07(m,2H),1.19-1.12(m,9H).LC-MS(ES+):m/z 431.11[MH+],tR＝0.73 And (3) minutes.
Intermediate 2 (2S, 4R) -1- [ (S) -2-amino-3, 3-dimethylbutyryl ] -4-hydroxy-N- [ (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl ] -pyrrolidine-2-carboxamide hydrochloride (ULM-2)
Step 1 preparation of (S) -tert-butyl-1- (4-bromophenyl) -ethylcarbamate
To a mixture of (S) -1- (4-bromophenyl) ethylamine (3.98 g,19.9 mmol) and NaHCO 3 (1.24 g,14.8 mmol) in H 2 O (10 mL) and ethyl acetate (10 mL) at 5℃was added (Boc) 2 O (5.20 g,23.8 mmol). The reaction was continued for 2 hours. TLC showed the reaction was complete. The reaction mixture was filtered. The solid was collected and suspended in a mixture of hexane (10 mL) and H 2 O (10 mL) for 0.5 hours. The mixture was filtered and the solid was collected and dried in an oven at 50 ℃ to give the title compound (5.9 g, 98.7%) as a white solid.
1HNMR(400MHz,DMSO-d6):δ1.28(d,J＝7.2Hz,3H),1.36(s,9H),4.55-4.60(m,1H),7.25(d,J＝8.4Hz,2H),7.39(br,1H),7.49(d,J＝8.4Hz,2H).
Step 2 preparation of (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethylamine hydrochloride
A mixture of (S) -tert-butyl-1- (4-bromophenyl) -ethylcarbamate (4.0 g,13.3 mmol), 4-methylthiazole (2.64 g,26.6 mmol), palladium (II) acetate (29.6 mg,0.13 mmol) and potassium acetate (2.61 g,26.6 mmol) in DMF (10 mL) was stirred at 90℃under N 2 for 18 hours. After cooling to ambient temperature, the reaction mixture was filtered. H 2 O (50 mL) was added to the filtrate, and the resulting mixture was stirred at ambient temperature for 4 hours. The reaction mixture was filtered. The solid was collected by filtration and dried in an oven at 50 ℃ to give (S) -tert-butyl-1- (4- (4-methylthiazol-5-yl) phenyl) ethylcarbamate (3.48 g, 82.3%) as a grey solid.
1HNMR(400MHz,DMSO-d6):δ1.33(d,J＝7.2Hz,3H),1.38(s,9H),2.46(s,3H),4.64-4.68(m,1H),7.23(br d,0.5H),7.39(d,J＝8Hz,2H),7.44(d,J＝8.4Hz,2H),7.50(br d,0.5H),8.99(s,1H);LC-MS[M+1]+:319.5
The solid material (1.9 g,6.0 mmol) was dissolved in a solution of 4N hydrochloride in methanol (5 mL,20mmol, prepared from acetyl chloride and methanol) and the mixture was stirred at ambient temperature for 3 hours, then concentrated and triturated with diethyl ether. The mixture was filtered and the solid was collected and dried in an oven at 60 ℃ to give (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethylamine hydrochloride (1.3 g, 85%) as a pale green solid.
1HNMR(400MHz,DMSO-d6):δ1.56(d,J＝6.8Hz,3H),2.48(s,3H),4.41-4.47(m,1H),7.57(d,J＝8.4Hz,2H),7.67(d,J＝8.4Hz),8.75(s,3H),9.17(s,1H);LC-MS[M+1]+:219.2
Step 3 preparation of (2S, 4R) -1- { (S) -2- [ (tert-Butoxycarbonyl) amino ] -3, 3-dimethylbutyryl } -4-hydroxypyrrolidine-2-carboxylic acid
HATU (2.15 g,5.7 mmol) was added to a solution of (S) -2- (tert-butoxycarbonyl) amino-3, 3-dimethylbutyric acid (1.25 g,5.4 mol), (2S, 4 r) -methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride (0.98 g,5.4 mmol) and DIPEA (2.43 g,18.9 mmol) in DMF (10 mL) under nitrogen at 0 ℃. The mixture was stirred at ambient temperature for 18 hours. TLC showed the reaction was complete. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (15 mL X4). The combined organic layers were washed with 5% citric acid (10 ml x 2), saturated NaHCO 3 solution (10 ml x 2), brine (10 ml x 2) and dried over Na 2SO4. The organic solution was filtered and concentrated to give (2S, 4 r) -methyl 1- { (S) -2- [ (tert-butoxycarbonyl) amino ] -3, 3-dimethylbutyryl } -4-hydroxypyrrolidine-2-carboxylate (1.93 g,100% yield) as a pale yellow oil. The crude product (1.93 g) and lithium hydroxide hydrate (2.2 g,54 mmol) were added to THF (20 mL) and H 2 O (10 mL). The resulting mixture was stirred at ambient temperature for 18 hours. THF was removed by concentration. The residue was diluted with ice water (10 mL) and slowly adjusted to pH 2-3 with 3N HCl. The resulting suspension was filtered and washed with H 2 O (6 mL. Times.2). The solid was collected by filtration and dried in an oven at 50 ℃ to give the title compound (1.4 g, 75% for both steps) as a white solid.
1HNMR(400MHz,DMSO-d6):δ6.50(d,J＝9.6Hz,1H),5.19(br s,1H),4.32(br s,1H),4.25(t,J＝8.4Hz,1H),4.16(d,J＝9.2Hz,1H),3.57-3.66(m,2H),2.08-2.13(m,1H),1.85-1.91(m,1H),1.38(s,9H),0.94(s,9H).
Step 4 preparation of (2S, 4R) -1- [ (S) -2-amino-3, 3-dimethylbutyryl ] -4-hydroxy-N- [ (S) -1- (4- (4-methylthiazol) -5-yl) phenyl) ethyl ] -pyrrolidine-2-carboxamide hydrochloride (ULM-2)
HATU (1.6 g,4.2 mmol) was added to a stirred solution containing (2S, 4 r) -1- { (S) -2- [ (tert-butoxycarbonyl) amino ] -3, 3-dimethylbutyryl } -4-hydroxypyrrolidine-2-carboxylic acid (1.21 g,3.5 mmol), (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethylamine hydrochloride (0.9 g,3.5 mmol) and DIPEA (1.36 g,10.5 mmol) in anhydrous THF (15 mL) at 0 ℃. The resulting mixture was allowed to warm up to ambient temperature and stirring was continued for 2 hours. TLC showed the reaction was complete. THF was removed by concentration. Water (15 mL) was added to the residue, and the resulting mixture was stirred for 4 hours. The resulting mixture was filtered. The solid was collected and dried in an oven at 50 ℃ to give a white solid. This solid was added to methanol (10 mL), and activated carbon (150 mg) was added. The resulting mixture was heated at 80 ℃ and stirred for 1 hour. The mixture was filtered while hot. Water (5 mL) was added to the filtrate at 80 ℃. The resulting mixture was cooled to ambient temperature and stirring was continued for 18 hours. The suspension was filtered. The solid was collected and dried in an oven at 50 ℃ to give tert-butyl- { (S) -1- [ (2S, 4 r) -4-hydroxy ] -2- [ (S) -1- (4- (4-methylthiazol-5-yl) phenyl) -ethylcarbamoyl ] pyrrolidin-1-yl } -3, 3-dimethyl-1-oxobutan-2-yl-carbamate (1.41 g, 74.2%) as a white solid.
1H NMR(400MHz,CDCl3):δ1.05(s,9H),1.42(s,9H),1.47(d,J＝7.2Hz,3H),2.04-2.10(m,1H),2.53(s,3H),2.58-2.64(m,1H),3.23(s,1H),3.58(dd,J＝11.2Hz,3.2Hz,1H),4.11(d,J＝11.6Hz,1H),4.22(d,J＝9.2Hz,1H),4.51(br,1H),4.79(t,J＝8.0Hz,1H),5.04-5.11(m,1H),5.22(d,J＝8.8Hz,1H),7.36-7.42(m,4H),7.61(d,J＝7.6Hz 1H),8.68(s,1H).
The solid (1.04 g,1.9 mmol) was dissolved in a solution of 4N hydrogen chloride in methanol (3.0 mL) and the mixture was stirred at ambient temperature for 3 hours. TLC showed the reaction was complete. The reaction mixture was concentrated to remove all volatiles under reduced pressure to give a pale yellow solid. The solid was added to TBME (5 mL) and the resulting mixture was stirred at ambient temperature for 4 hours. The reaction mixture was filtered and the solid was collected and dried in an oven at 50 ℃ to give the title compound (0.92 g, 100%).
1H NMR(400MHz,DMSO-d6):δ1.03(s,9H),1.38(d,J＝7.2Hz,3H),1.72-1.79(m,1H),2.09-2.14(m,1H),2.49(s,3H),3.48-3.52(m,1H),3.75-3.79(m,1H),3.88-3.90(m,1H),4.31(br,1H),4.56(t,J＝8.4Hz,1H),4.89-4.95(m,1H),7.41(d,J＝8.4Hz,2H),7.47(d,J＝8.4Hz,2H),8.20(br,3H),8.67(d,J＝7.6Hz,1H),9.22(s,1H);13C NMR(400MHz,DMSO-d6):δ170.7,167.1,153.0,146.5,145.7,132.5,129.4,129.3,126.9,69.4,59.3,58.5,56.9,48.3,38.4,34.8,26.6,23.0,15.7;LC-MS[M+1]+:445.6
Intermediate 3 (2S, 4R) -4-hydroxy-N- (2-hydroxy-4- (4-methylthiazol-5-yl) benzyl) -1- ((S) -3-methyl-2- (1-oxoisoindolin-2-yl) butanoyl) pyrrolidine-2-carboxamide (ULM-3)
Step 1 preparation of 2-hydroxy-4- (4-methylthiazol-5-yl) benzonitrile
A mixture of 4-bromo-2-hydroxybenzonitrile (15 g,76 mmol), 4-methylthiazole (14 mL,152 mmol), KOAc (14.9 g,152 mmol) and Pd (OAc) 2 (0.34 g,1.52 mmol) in anhydrous NMP (125 mL) was stirred at 110℃under nitrogen atmosphere for 6 hours. TLC showed the reaction was complete. The mixture was first cooled to room temperature and then partitioned between EtOAc and water. The combined organic fractions were filtered and the filtrate was washed with water, brine, dried over anhydrous Na 2SO4 and concentrated. The residue was dissolved in toluene (100 mL) and evaporated again to give a crude product. The crude product was treated with cold MeOH (80 mL). The resulting precipitate was collected by filtration, washed with MeOH (20 mL), and dried under vacuum to give the title compound (10.5 g, 64%) as a pale yellow solid.
LC/MS:217.2[M+1]+.
1HNMR(400MHz,DMSO-d6):δ2.49(s,3H),7.07(dd,J＝8.0,1.6Hz,1H),7.13(d,J＝1.6Hz,1H),7.70(d,J＝8.0Hz,1H),9.07(s,1H),11.34(s,1H).
Step 2 preparation of 2- (aminomethyl) -5- (4-methylthiazol-5-yl) phenol
To a solution of 2-hydroxy-4- (4-methylthiazol-5-yl) benzonitrile (2.9 g,13.41 mmol) in anhydrous THF (150 mL) at 0deg.C was added LiAlH 4 (1.5 g,40.23 mmol) in portions. The resulting mixture was stirred at 50 ℃ under nitrogen atmosphere for 3 hours. TLC showed the reaction was complete. The mixture was cooled in an ice-water bath, then Na 2SO4·10H2 O (5 g) was carefully added and stirred at this temperature for 1 hour. The mixture was filtered and the filter cake was washed four times with 10% meoh in DCM. The combined filtrates were concentrated to give crude 2- (aminomethyl) -5- (4-methylthiazol-5-yl) phenol as a pale yellow solid, (2.0 g, 68%). It was used in the next step without further purification.
LCMS:221.2[M+H]+.
1HNMR(400MHz,DMSO-d6):δ2.43(s,3H),3.54(br,2H),6.11(d,J＝7.2Hz,1H),6.40(d,J＝11.6Hz,1H),6.83(d,J＝7.6Hz,1H),8.81(s,1H).
Step 3 preparation of (S) -3-methyl-2- (1-oxoisoindolin-2-yl) butanoic acid
L-valine (4.37 g,37.3 mmol) was added to a solution of phthalic aldehyde (5.0 g,37.3 mmol) in acetonitrile (350 mL). The resulting mixture was refluxed for 5 hours. The reaction mixture was filtered while hot and the filtrate was slowly cooled to room temperature. The resulting precipitate was filtered and dried to give (S) -3-methyl-2- (1-oxoisoindolin-2-yl) butanoic acid (6.45 g, 74%) as a white solid.
1HNMR(400MHz,DMSO-d6):δ0.85(d,J＝6.8Hz,3H),1.0(d,J＝6.8Hz,3H),2.25-2.34(m,1H),4.51(d,J＝4.4Hz,1H),4.54(d,J＝3.6Hz,1H),4.64(d,J＝18.0Hz,1H),7.48-7.54(m,1H),7.63(d,J＝3.6Hz,2H),7.72(d,J＝7.6Hz,1H),13.01(br,1H).
Step 4 preparation of (2S, 4R) -4-hydroxy-1- ((S) -3-methyl-2- (1-oxoisoindolin-2-yl) butanoyl) pyrrolidine-2-carboxylic acid ester
To a solution of 4-hydroxy-L-proline methyl ester hydrochloride (1.0 g,5.52 mmol), (S) -3-methyl-2- (1-oxoisoindolin-2-yl) butyric acid (1.16 g,4.97 mmol) and DIPEA (2.58 g,20 mmol) in anhydrous DMF (15 mL) at 0℃was added HATU (3.8 g,10 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was partitioned between EtoAc and water. The organic phase was washed with water, brine and dried over anhydrous Na 2SO4. The residue was purified by silica gel chromatography using 30-50% etoac in hexane as eluent to give the title compound (1.21 g, 67.6%) as a pale yellow solid.
LCMS:361.3[M+1]+.
Step 5 preparation of (2S, 4R) -4-hydroxy-1- ((S) -3-methyl-2- (1-oxoisoindolin-2-yl) butanoyl) pyrrolidine-2-carboxylic acid
A mixture containing (2S, 4R) -methyl 4-hydroxy-1- ((S) -3-methyl-2- (1-oxoisoindolin-2-yl) butyryl) pyrrolidine-2-carboxylate (1.2 g,3.33 mmol), liOH. H 2 O (559 mg,13.32 mmol) in THF (20 mL) and H 2 O (10 mL) was stirred at room temperature for 2 hours. TLC showed the reaction was complete. The reaction mixture was acidified to pH 1-2 with 1N HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na 2SO4 and concentrated to give the title compound as a pale yellow solid (1.05 g,91% yield).
1HNMR(400MHz,CDCl3):δ0.91(d,J＝6.4Hz,3H),1.05(d,J＝6.8Hz,3H),2.30(dd,J＝8.4,2.8Hz,2H),2.44-2.50(m,1H),3.75(dd,J＝11.2,3.2Hz,1H),4.42(d,J＝17.6Hz,1H),4.50-4.55(m,2H),4.66(t,J＝8.4Hz,1H),4.75(d,J＝17.6Hz,1H),4.83(d,J＝11.2Hz,1H),7.42-7.45(m,2H),7.51-7.56(m,1H),7.78(d,J＝7.6Hz,1H).
Step 6 preparation of (2S, 4R) -4-hydroxy-N- (2-hydroxy-4- (4-methylthiazol-5-yl) benzyl) -1- ((S) -3-methyl-2- (1-oxoisoindolin-2-yl) butanoyl) pyrrolidine-2-carboxamide
To a solution of (2S, 4 r) -4-hydroxy-1- ((S) -3-methyl-2- (1-oxoisoindolin-2-yl) butyryl) pyrrolidine-2-carboxylic acid (1.0 g,2.89 mmol), 2- (aminomethyl) -5- (4-methylthiazol-5-yl) phenol (954 mg,4.33 mmol) and DIPEA (1.5 g,11.55 mmol) in DMF (20 mL) at 0 ℃ was added HATU (2.2 g,5.77 mmol). The resulting mixture was stirred at room temperature for 1 hour. TLC showed the reaction was complete. The mixture was partitioned between EtoAc and water. The organic phase was washed with water, brine and dried over anhydrous Na 2SO4. The residue was purified by column chromatography on silica gel using 2-5% meoh in DCM to give the title compound as a pale yellow solid (650 mg,43% yield).
LCMS:549.2[M+H]+
1HNMR(400MHz,CDCl3):δ0.80(d,J＝6.8Hz,3H),0.88(d,J＝6.8Hz,3H),1.96-2.01(m,1H),2.34-2.40(m,1H),2.47-2.53(m,4H),3.61(dd,J＝11.6,3.6Hz,1H),4.29-4.37(m,2H),4.38-4.41(m,1H),4.47-4.50(m,2H),4.64-4.69(m,2H),4.72(s,1H),6.90(dd,J＝8.0,2.0Hz,1H),7.01(d,J＝2,0Hz,1H),7.14(d,J＝8.0Hz,1H),7.39-7.44(m,2H),7.51-7.54(m,1H),7.76(d,J＝7.6Hz,1H),8.03(t,J＝6.4Hz,1H),8.66(s,1H),9.27(br,1H).
Intermediate 4 (2R, 4S) -1- [ (S) -2-amino-3, 3-dimethylbutyryl ] -4-hydroxy-N- [ (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl ] -pyrrolidine-2-carboxamide hydrochloride (ULM-4)
The compound was synthesized using (2R, 4S) -methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride using the same procedure as described in the preparation of ULM-2 .1HNMR(400MHz,CD3OD):δ1.14(s,9H),1.55(d,J＝6.8Hz,3H),2.00-2.05(m,1H),2.51-2.58(m,1H),2.65(s,3H),3.77-3.81(m,1H),3.88-3.92(m,1H),4.06(br,1H),4.41-4.46(m,1H),4.56-4.60(m,1H),5.07-5.12(m,1H),7.58(d,J＝8.0Hz,2H),7.67(d,J＝8.0Hz,2H),10.02(s,1H).LC-MS[M+H]+:445.3
Intermediate 5 and intermediate 6 tert-butyl-N- [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- { [ (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl ] carbamoyl } pyrrolidin-1-yl ] -3, 3-dimethyl-1-oxobutan-2-yl ] carbamate (ULM-5-A) and tert-butyl N- [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- { [ (1S) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl ] carbamoyl } pyrrolidin-1-yl ] -3, 3-dimethyl-1-oxobutan-2-yl ] carbamate (ULM-5-B)
Step 1 Synthesis of 2- (4-bromophenyl) oxirane
A mixture of 4-bromobenzaldehyde (2.52 g,13.6 mmol), trimethylsulfonium iodide (2.87 g,14.1 mmol), water (0.65 mL,36.1 mmol) and potassium hydroxide (1.56 g,27.7 mmol) in acetonitrile (20 mL) was warmed to 55℃for a total of 4 hours. The resulting solution was partitioned between water and diethyl ether, and the organic layer was washed with water, dilute hydrochloric acid and brine, and dried over sodium sulfate. The crude product of 2- (4-bromophenyl) oxirane (2.20 g,81.8% yield) was obtained by removal of the organic solvent under reduced pressure, which was used for the next reaction without purification.
1H NMR(400MHz,CDCl3)δ2.74(1H,q,J＝2.8Hz),3.14(1H,dd,J＝4.0Hz,5.2Hz),3.82(1H,dd,J＝2.4Hz,4.0Hz),7.15(2H,d,J＝8.4Hz),7.47(2H,d,J＝8.8Hz).
Step 2 Synthesis of 2-azido-2- (4-bromophenyl) ethanol
To a stirred suspension of 2- (4-bromophenyl) oxirane (5.0 g,25.3 mmol) in distilled water (70 mL) was added sodium azide (3.28 g,50.5 mmol), and the resulting mixture was stirred at 60℃for 4 hours and monitored by TLC. After completion of the reaction, the mixture was extracted with EtOAc, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 2-azido-2- (4-bromophenyl) ethanol (5.5 g, 90.2%) as a pale yellow oil. The crude product was used directly in the next step.
1H NMR(400MHz,CDCl3)δ1.94(1H,s),3.63-3.66(2H,m),4.57(1H,dd,J＝5.2Hz,7.6Hz),7.15(2H,d,J＝8.4Hz),7.46(2H,d,J＝8.4Hz).
Step 3 Synthesis of 2-amino-2- (4-bromophenyl) ethanol hydrochloride
To a solution of 2-azido-2- (4-bromophenyl) ethanol (2.0 g,8.30 mmol) in tetrahydrofuran (20.0 mL) and water (5.00 mL) was added triphenylphosphine (4.35 g,16.6 mmol). The reaction mixture was stirred at room temperature overnight and the solvent was removed in vacuo. The residue was dissolved in HCl/dioxane (4 m,10.0 ml) and stirred at room temperature for 1 hour. After concentration, the solid was washed with dichloromethane to give 2-amino-2- (4-bromophenyl) ethanoic acid hydrochloride (1.5 g,72.1% yield) as a white solid.
1H NMR(400MHz,CDCl3)δ3.70(2H,s),4.28(1H,s),5.55(1H,s),7.47(2H,d,J＝8.4Hz),7.63(2H,d,J＝8.4Hz),8.61(3H,s);LC/MS 216.2[M+H]+.
Step 4 Synthesis of 1- (4-bromophenyl) -2- (t-butyldimethylsilyloxy) ethylamine
To a solution of 2-amino-2- (4-bromophenyl) ethanol hydrochloride (1.80 g,7.17 mmol) in methylene chloride (50 mL) at room temperature was added imidazole (1.95 g,2.87 mmol) and t-butyldimethylchlorosilane (TBSCl) (1.63 g,10.8 mmol). The reaction mixture was stirred at room temperature overnight and then quenched with water. The aqueous phase was extracted with dichloromethane (30 ml x 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude compound. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5:1) to give 1- (4-bromophenyl) -2- (tert-butyldimethylchlorosilane) ethanamine (1.50 g, 63.6%) as a white solid.
LC/MS:330.1[M+H]+;
Step 5 Synthesis of tert-butyl 1- (4-bromophenyl) -2- (tert-butyldimethylsilyloxy) ethylcarbamate
To a solution of 1- (4-bromophenyl) -2- (t-butyldimethylsilyloxy) ethylamine (1.50 g,4.56 mmol) in tetrahydrofuran (20 mL) were added triethylamine (0.69 g,6.84 mmol) and di-t-butyldicarbonate (1.49 g,6.84 mmol). The reaction mixture was stirred at room temperature overnight and then quenched with water. The aqueous phase was extracted with ethyl acetate (50 ml x 3) and washed with brine. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude compound. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:1) to give tert-butyl 1- (4-bromophenyl) -2- (tert-butyldimethylsilyloxy) ethylcarbamate (1.80 g, 92.0%) as a pale yellow oil.
1H NMR(400MHz,CDCl3)δ0.01(6H,d,J＝9.6Hz),0.86(9H,s),1.42(9H,s),3.65-3.70(2H,m),4.60-4.63(1H,m),7.34(2H,d,J＝8.0Hz),7.39(1H,d,J＝8.8Hz),7.56(2H,d,J＝8.4Hz).
Step 6 Synthesis of tert-butyl 2-hydroxy-1- (4- (4-methylthiazol-5-yl) phenyl) -ethylcarbamate
A mixture of tert-butyl 1- (4-bromophenyl) -2- (tert-butyldimethylsilyloxy) ethylcarbamate (4.0 g,9.32 mmol), 4-methylthiazole (1.85 g,18.6 mmol), potassium acetate (1.82 g,18.6 mmol), palladium (II) acetate (0.11 g,0.47 mmol) was dissolved in dimethylacetamide and stirred under argon. The mixture was heated to 140 ℃ and stirred for 15 hours, then diluted with water. The aqueous phase was extracted with ethyl acetate (50 ml x 3) and washed with brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give the crude compound which was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:1) to give tert-butyl 2-hydroxy-1- (4- (4-methylthiazol-5-yl) phenyl) ethylcarbamate (1.30 g, 41.8%) as a pale yellow solid.
1H NMR(400MHz,CDCl3)δ1.38(9H,s),2.46(3H,s),3.52(2H,t,J＝6.0Hz),4.55-4.58(1H,m),4.84(1H,t,J＝6.0Hz),7.30(1H,d,J＝8.0Hz),7.38-7.45(4H,m),8.99(1H,s);LC/MS 335.2[M+H]+;Rt＝1.859 Minute (min)
Step 7 Synthesis of 2-amino-2- (4- (4-methylthiazol-5-yl) phenyl) ethanoate hydrochloride
Tert-butyl 2-hydroxy-1- (4- (4-methylthiazol-5-yl) phenyl) ethylcarbamate (300 mg,0.536 mmol) was dissolved in hydrochloric acid/dioxane (5 ml,4 m). The resulting reaction mixture was stirred at room temperature for 3 hours. The solvent was concentrated in vacuo to give 2-amino-2- (4- (4-methylthiazol-5-yl) phenyl) ethanoate as a white solid which was used in the next step without further purification.
Step 8 Synthesis of tert-butyl N- [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- { [ (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl ] carbamoyl } pyrrolidin-1-yl ] -3, 3-dimethyl-1-oxobutan-2-yl ] carbamate (ULM-5-A) and tert-butyl N- [ (2S) -1- [ (2S, 4R) -4-hydroxy-2- { [ (1S) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl ] carbamoyl } pyrrolidin-1-yl ] -3, 3-dimethyl-1-oxobutan-2-yl ] carbamate (ULM-5-B)
A solution of 2-amino-2- (4- (4-methylthiazol-5-yl) phenyl) ethanol hydrochloride (1000 mg,3.70 mmol), N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (EDCI) (995 mg,5.19 mmol), 1-Hydroxybenzotriazole (HOBT) (695 mg,5.19 mmol), (2S, 4R) -1- ((S) -2- (tert-butoxycarbonylamino) -3, 3-dimethylbutyryl) 4-hydroxypyrrolidine-2-carboxylic acid (1273 mg,3.70 mmol) and triethylamine (747 mg,7.40 mmol) in N, N-dimethylformamide (50 mL) was stirred overnight at room temperature under argon, then water (80 mL) was added to the mixture. The aqueous layer was extracted with ethyl acetate (50 ml x 5). The combined organic layers were washed with brine (50 ml x 3), dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by preparative TLC (dichloromethyl/methanol=15:1) to give tert-butyl (S) -1- ((2S, 4R) -4-hydroxy-2- ((R) -2-hydroxy-1- (4- (4-methylthiazol-5-yl) phenyl) ethylcarbamoyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-ylcarbamate (700 mg) as pale yellow oil, and tert-butyl (S) -1- ((2S, 4R) -4-hydroxy-2- ((S) -2-hydroxy-1- (4- (4-methylthiazol-5-yl) phenyl) ethylcarbamoyl) pyrrolidin-1- α) -3, 3-dimethyl-1-oxobutan-2-ylcarbamate (500 mg) as pale yellow oil.
ULM-5-A：1H NMR(400MHz,CDCl3)δ0.93(9H,s),1.39(9H,s),1.77-1.83(1H,m),2.01-2.06(1H,m),2.46(3H,s),3.54-3.60(4H,m),4.13-4.19(1H,m),4.29-4.36(1H,m),4.50(1H,t,J＝8.0Hz),4.78(1H,t,J＝5.6Hz),4.81-4.88(1H,m),5.12-5.16(1H,m),6.46(1H,d,J＝9.2Hz),7.36-7.46(4H,m),8.41(1H,d,J＝8.0Hz),8.99(1H,s);LC/MS 561.2[M+H]+;Rt＝1.897min
ULM-5-B：1H NMR(400MHz,CDCl3)δ0.87(9H,s),1.38(9H,s),1.92-2.06(2H,m),2.45(3H,s),3.56-3.69(4H,m),4.06-4.14(1H,m),4.36(1H,s),4.56(1H,t,J＝7.6Hz),4.76-4.81(1H,m),4.87(1H,t,J＝5.6Hz),5.146(1H,d,J＝2.8Hz),6.47(1H,d,J＝8.8Hz),7.37(2H,d,J＝8.0Hz),7.51(2H,d,J＝8.0Hz),8.37(1H,d,J＝7.6Hz),8.98(1H,s);LC/MS 561.2[M+H]+;Rt＝1.887 Minute (min)
Intermediate 7 (2S, 4R) -N- [ (4-chloro-2-hydroxyphenyl) methyl ] -4-hydroxy-1- [ 3-methyl-2- (3-methyl-1, 2-oxazol-5-yl) butanoyl ] pyrrolidine-2-carboxamide (ULM-6)
This key intermediate was prepared using the synthetic route described above. The desired 3-methylisoxazole-5-acetic acid was prepared according to literature (J.org.chem.66, 6595-6603,2001). Alkylation with 2-iodopropane has been described in the literature. The desired ULM-6 was prepared using the same synthetic procedure as described for the preparation of intermediate ULM-3.
1H NMR(400MHz,CDCl3):δ9.33(s,0.5H),9.20(s,0.5H),8.07(t,J＝6.4Hz,0.5H),7.83(t,J＝6.0Hz,0.5H),6.99(dd,J＝2.4,8.0Hz,1H),6.89-6.90(m,1H),6.76-6.78(m,1H),6.02(s,0.5H),5.99(s,0.5H),5.80-5.83(m,0.5H),4.35(q,J＝6.4Hz,1.5),4.16-4.25(m,2H),3.72-3.76(m,0.5H),3.61(d,J＝9.2Hz,1.0H),3.51-3.55(m,1.5H),2.30-2.46(m,2.5H),2.26(s,1.5H),2.24(s,1.5H),1.95-2.05(m,1H),1.01(d,J＝6.8Hz,1.5H),0.82-0.87(m,4.5H);LC-MS 436.1[M+1]+;Rt＝3.57 And (3) minutes.
PTM synthesis:
Preferred PTM embodiments of the present disclosure can be prepared according to the synthetic routes set forth in schemes 1-3 below. These pathways may be modified using general methods known to those skilled in the art and are suitable for the synthesis of specific PTM embodiments.
Exemplary PROTAC Synthesis:
Intermediate 1
Step 12- (2, 6-Dioxopiperidin-3-yl) -5- (2- (2- (2-hydroxyethoxy) ethoxy) isoindoline-1, 3-dione
To a solution of 2- (2, 6-dioxopiperidin-3-yl) -5-hydroxyisoindoline-1, 3-dione (500 mg,1.82 mmol) in DMF (10 mL) at 25℃was added K 2CO3 (756 mg,5.47 mmol) and 2- (2- (2-hydroxyethoxy) ethoxy) ethyl 4-methyl-benzenesulfonate (832 mg,2.73 mmol). The resulting solution was stirred at 70 ℃ for 5 hours. After cooling to room temperature, the reaction was quenched with H 2 O (10 mL) and the mixture was extracted with EtOAc (10 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give the desired product (95 mg,13% yield).
Step 2- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) ethoxy) acetaldehyde
To a solution of 2- (2, 6-dioxopiperidin-3-yl) -5- (2- (2- (2-hydroxyethoxy) ethoxy) isoindoline-1, 3-dione (95 mg, 0.23) in CH 3 CN (5 mL) at 25℃was added IBX (130 mg,0.46 mmol). The reaction was stirred at 80 ℃ for 2 hours. After cooling to room temperature, the mixture was filtered through celite and the filtrate was concentrated to give the crude intermediate 1,2- (2- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) ethoxy) acetaldehyde (90 mg) which was used without further purification.
Intermediate 2
To a solution of 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (10 g,36.2 mmol) in NMP (70 mL) was added tert-butylpiperazine-1-carboxylate (13.47 g,72.5 mmol) and DIPEA (18.6 g,14.5 mmol). The resulting mixture was stirred at 90 ℃ for 16 hours. After cooling to room temperature, the reaction was quenched with water (100 mL) and the mixture was extracted with ErOAc (300 mL x 2). The combined organic layers were dried over Na 2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/ea=100-2/1) to give the desired product 2- (2, 6-dioxopiperidin-3-yl) -5- (piperazin-1-yl) isoindoline-1, 3-dione (14 g,31.67mmol,87.5% yield) as a pale yellow solid.
Synthetic scheme for exemplary Compound 51
Step 1 3- (4-bromophenyl) -4-nitropyridine
To a stirred solution of 3-bromo-4-nitropyridine (100 g,492.6 mmol), (4-bromophenyl) boronic acid (98.6 g,492.6 mmol) and potassium carbonate (203.9 g,1.47 mol) in toluene (1000 ml) -water (100 ml) at room temperature under nitrogen atmosphere was added tetrakis (triphenylphosphine) palladium (14.8 g,12.8 mmol), and the mixture was degassed three times with nitrogen. The resulting mixture was stirred at 50 ℃ overnight. TLC showed the reaction was complete. The solids were removed by filtration and washed with ethyl acetate (100 ml x 3). The organic layer was collected and the aqueous layer was extracted with ethyl acetate (100 ml x 2). The combined organic layers were washed with brine (400 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by a pad of silica gel (eluting with 10-33% ethyl acetate in hexane) to give 3- (4-bromophenyl) -4-nitropyridine as a yellow solid (89 g, 65% yield).
Step 2 7-bromo-5H-pyrido [4,3-b ] indole
A mixture of 3- (4-bromophenyl) -4-nitropyridine (20.0 g,71.7 mmol) in triethyl phosphate (400 ml) was stirred at 110℃for 2 hours under nitrogen atmosphere. TLC showed the reaction was complete. The volatiles were evaporated under reduced pressure to give a residue which was purified by recrystallization (methanol) to give 7-bromo-5H-pyrido [4,3-b ] indole (11.0 g, 62% yield) as a brown solid.
Step 3 7- (6-Fluoropyridin-3-yl) -5H-pyrido [4,3-b ] indole
A mixture of 7-bromo-5H-pyrido [4,3-b ] indole (400 mg,1.63 mmol), (6-fluoropyridin-3-yl) boronic acid (344 mg,2.44 mmol), pdCl 2(dppf)(120mg,0.163mmol)、tBu3PHBF4 (95 mg,0.326 mmol) and Cs 2CO3 (1.1 g,3.26 mmol) in dioxane/water (20 mL, 20:1) was heated to 90℃under N 2 for a total of 4 hours. The solid was filtered and the filtrate evaporated. The residue was purified by chromatography (silica gel, 200-300 mesh, CH 2Cl2: meoh=30:1)) to give 7- (6-fluoropyridin-3-yl) -5H-pyrido [4,3-b ] indole (250 mg,59% yield).
Step 4 14- (5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxaundecan-1-ol
To a solution of 3,6,9, 12-tetraoxatetradecane-1, 14-diol (270 mg,1.13 mmol) in THF (10 mL) at 0deg.C was added NaH (45 mg,60%,1.13 mmol). After stirring at 20℃for 1 hour, a solution of 7- (6-fluoropyridin-3-yl) -5H-pyrido [4,3-b ] indole (150 mg,0.57 mmol) in DMF (2.0 mL) was added. The resulting solution was stirred at 80 ℃ for 4 hours. After cooling to room temperature, the reaction was diluted with EA (30 mL) and the mixture was washed with brine. The organic phase was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM/meoh=4/1) to give the desired product as a colourless oil (200 mg,72.89% yield).
Step 5 tert-butyl 7- (6- ((14-hydroxy-3, 6,9, 12-tetraoxatetradecyl) oxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole-5-carboxylate
To a solution of 14- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxaundecan-1-ol (150 mg,0.31 mmol) in DCM (10 mL) was added NEt 3 (94.5 mg,0.93 mmol) and Boc 2 O (102.0 mg,0.47 mmol). The resulting solution was stirred at ambient temperature for 12 hours. The solvent was removed under vacuum. The residue was diluted with EA (30 mL), and the mixture was washed with brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to give the desired product (120 mg,66% yield) which was used in the next step without further purification.
Step 6 tert-butyl 7- (6- ((14- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole-5-carboxylate
To a solution of tert-butyl 7- (6- ((14-hydroxy-3, 6,9, 12-tetraoxatetradecyl) oxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole-5-carboxylate (120 mg,0.31 mmol) and NEt 3 (93.9 mg,0.93 mmol) in DCM (10 mL) at 0℃was added MsCl (38.9 mg,0.34 mmol). After stirring for 1 hour at 30 ℃, the solvent was removed. The residue was diluted with EA (30 mL) and washed with brine. The organic phase was concentrated to give the intermediate mesylate.
To a stirred solution of methanesulfonate (100 mg,0.15 mmol) in anhydrous DMF (10 mL) was added 2- (2, 6-dioxopiperidin-3-yl) -5-hydroxyisoindoline-1, 3-dione (45.6 mg,0.17 mmol) and K 2CO3 (31.4 mg,0.23 mmol). The resulting mixture was stirred at 68 ℃ for 4 hours. The mixture was diluted with EtOAc (40 mL), washed twice with brine, and dried over anhydrous sodium sulfate. The organic phase was evaporated under reduced pressure. The residue was purified by preparative TLC (DCM/meoh=20/1) to give the desired product as a yellow solid (15 mg,23.6% yield).
Step 7:5- ((14- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
To a solution of tert-butyl 7- (6- ((14- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole-5-carboxylate (30 mg,0.036 mmol) in DCM (2 mL) was added TFA (5 mL). The mixture was stirred at ambient temperature for 4 hours. The mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC to give the title compound as a white solid (10 mg,38% yield ).1H NMR(400MHz,CDCl3):δ12.34–12.48(m,1H),9.19–9.29(m,1H),8.80(s,1H),8.29–8.42(m,1H),8.02–8.14(m,1H),7.95(s,1H),7.69–7.81(m,1H),7.60(s,2H),7.17(s,1H),7.09(s,1H),6.62(s,1H),4.97(s,1H),4.43(s,2H),4.14(s,2H),3.88(d,J＝24.1Hz,3H),3.78(d,J＝8.2Hz,3H),3.69(d,J＝10.0Hz,6H),2.80(m,4H),1.99–2.29(m,4H).(M+H)+ 738.3.
Compound 50 was also prepared using a procedure similar to compound 51.
Synthetic scheme for exemplary Compound 52
Step 1 t-butyl 4- (2-hydroxyethyl) piperazine-1-carboxylate
A solution of 2- (piperazin-1-yl) ethanol (5 g,38.5 mmol) and TEA (12 g,115 mmol) was stirred in DCM at 0deg.C, boc 2 O was added and the mixture was stirred overnight at 10deg.C. Water was added. The mixture was then extracted with DCM, dried and concentrated, and filtered through a pad of silica gel to give 8.1g of product (92% yield).
Step 2 tert-butyl 4- (2- (prop-2-yn-1-yloxy) ethyl) piperazine-1-carboxylate
A solution of tert-butyl 4- (2-hydroxyethyl) piperazine-1-carboxylate (3 g,13 mmol) in THF was stirred at 0 ℃. NaH (624 mg,15.6 mmol) was added and the mixture was stirred at room temperature for 1 hour. 3-Bromoprop-1-yne (1.85 g,15.6 mmol) was added and stirring was continued overnight at 70 ℃. The mixture was then cooled to room temperature. Water was added, then the mixture was extracted with EA, dried over Na 2SO4 and concentrated. Filtration through a pad of silica gel (EA) gave 1.5g of product (43% yield).
Step 3 tert-butyl 4- (2- ((3- (5-bromopyridin-2-yl) prop-2-yn-1-yl) oxy) ethyl) piperazine-1-carboxylate
Tert-butyl 4- (2- (prop-2-yn-1-yloxy) ethyl) piperazine-1-carboxylate (500 mg,1.86 mmol), 2, 5-dibromopyridine (442 mg,1.86 mmol), pd (PPh 3)2Cl2 (10%), cuI (11%), DIPEA and CH 3 CN were stirred overnight at 5 ℃ and the mixture was washed with water by addition EA., concentrated and then filtered through silica gel (EA) to give 450mg of product (57% yield).
Step 4 tert-butyl 4- (2- (3- (5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) propoxy) ethyl) piperazine-1-carboxylate
7- (4, 5-Tetramethyl-1, 3, 2-dioxaborane-2-yl) -5H-pyrido [4,3-b ] indole-5-carboxylic acid ester [ prepared by using a procedure similar to step 1 of exemplary compound 63 ] (300 mg,0.76 mmol), pd (am phose) Cl 2 (50 mg, 10%) and CsF (450 mg,2.96 mmol) were stirred in CH 3CN/H2 O (10:1) at 120℃for 40min in a microwave oven. The mixture was cooled to room temperature and EA was added. The organic layer was washed with water and then filtered through a pad of silica gel (DCM: meoh=20:1) to give 100mg of tert-butyl 4- (2- (3- (5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) prop-2-ynyloxy) ethyl) piperazine-1-carboxylate. The crude product was dissolved in MeOH, pd/C was added and the mixture was stirred at 30 ℃ under 2Mpa H 2 for 2 hours, filtered and concentrated to give 100mg of product (26% yield).
Step 5 7- (6- (3- (2- (piperazin-1-yl) ethoxy) propyl) pyridin-3-yl) -5H-pyrido [4,3-b ] indole
Tert-butyl 4- (2- (3- (5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) propoxy) ethyl) piperazine-1-carboxylate (100 mg,0.2 mmol) in HCl/dioxane solution (2 mL) was stirred at 5 ℃ for 1 hour. Concentrated to give 100mg of crude product.
Step 6 5- ((5- (4- (2- (3- (5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) propoxy) ethyl) piperazin-1-yl) pentyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione)
5- (2, 6-Dioxopiperidin-3-yl) -1, 3-Dioxoisoindolin-5-yloxy) valeraldehyde (86 mg,0.24 mmol), naBH 4 CN (55 mg,0.48 mmol) and CH 3 COOH (saturated) were stirred in MeOH at 5℃for 3 hours. DCM was then added. The organic layer was washed with water, concentrated, and filtered through a pad of silica gel (DCM: meoh=8:1) to give 11mg of product.
1HNMR(400MHz,MeOD):δ9.25(s,1H),8.79(s,1H),8.37-8.39(d,J＝8Hz,1H),8.28-8.30(d,J＝8Hz,1H),8.11-8.13(d,J＝8Hz,1H),7.80(s,1H),7.75-7.77(d,J＝8Hz,1H),7.60(s,1H),7.49-7.51(d,J＝8Hz,1H),7.43-7.45(d,J＝8Hz,1H),7.33(s,1H),5.07-5.09(m,1H),4.06-4.09(m,2H),3.57-3.60(m,2H),3.51-3.54(m,2H),2.93-2.95(m,2H),2.91-2.93(m,1H),2.59-2.75(m,12H),2.37-2.41(m,2H),2.04-2.06(m,3H),1.78-1.80(m,2H),1.46-1.55(m,5H).(M+H)+ 758.3.
Synthetic scheme for exemplary Compound 53
Step 1(((1 s,3 s) -3- (allyloxy) cyclobutoxy) methyl) benzene
To a solution of (1 s,3 s) -3- (benzyloxy) cyclobutanol (1.0 g,5.61 mmol) in DMF (10 mL) was added NaH (60%, 0.336g,8.4 mmol) at 0deg.C. After stirring for 30 minutes, 3-bromoprop-1-ene was added dropwise at room temperature. The resulting solution was stirred at room temperature for 3 hours. After it was quenched with saturated solution NH 4 Cl (20 mL), the mixture was extracted with EtOAc (20 mL. Times.2). The combined organic layers were dried over Na 2SO4 and concentrated in vacuo. The residue was purified by a silica gel column with PE/ea=10 to 1 as eluent to give the desired product (1.0 g, 82%) as a colourless oil.
Step 2:3- ((1 s,3 s) -3- (benzyloxy) cyclobutoxy) propan-1-ol
To a solution of (((1 s,3 s) -3- (allyloxy) cyclobutoxy) methyl) benzene (1.0 g,4.58 mmol) in THF (20 mL) at 0deg.C was added dicyclohexylborane in THF (1.0M, 9.0 mL). After it was stirred at room temperature for 4 hours, naOH (37%, 3.0 mL) and H 2O2 (30%, 3.0 mL) were added to the mixture at 0 ℃. The resulting solution was stirred at room temperature overnight. The reaction was quenched with Na 2S2O3 (20 mL). The mixture was taken up in DCM. The organic phase was dried over Na 2SO4 and concentrated in vacuo. The residue was purified on a silica gel column with PE/ea=2:1 as eluent to give the desired product (1.0 g, 100%) as a colourless oil.
Step 3 t-butyl 4- (3- ((1 s,3 s) -3- (benzyloxy) cyclobutoxy) propyl) piperazine-1-carboxylate
To a solution of 3- ((1 s,3 s) -3- (benzyloxy) cyclobutoxy) propan-1-ol (1.0 g,4.58 mmol) and TEA (2.0 g,19.8 mmol) in DCM (10 mL) at 0deg.C was added MsCl (0.97 g,9.2 mmol). After stirring at room temperature for 2 hours, the reaction was quenched with saturated solution of sodium bicarbonate (20 mL) and the mixture was extracted with DCM (20 mL x 2). The combined organic layers were dried over Na 2SO4 and concentrated in vacuo to give the desired product (1.1 g, crude) which was used in the next reaction without further purification.
To a solution of the above intermediate (1.1 g, crude) in DMF (10 mL) was added tert-butylpiperazine-1-carboxylate (1.60 g,9.2 mmol). The resulting solution was heated to 90 ℃ for a total of 4 hours. After cooling to room temperature, the reaction was quenched with water (20 mL) and the mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na 2SO4 and concentrated in vacuo. The residue was purified by silica gel column with PE/ea=2:1 as eluent to give the desired product (480 mg, 58%) as colourless oil.
Step 4 t-butyl 4- (3- ((1 s,3 s) -3-hydroxycyclobutoxy) propyl) piperazine-1-carboxylate
A mixture of tert-butyl 4- (3- ((1 s,3 s) -3- (benzyloxy) cyclobutoxy) propyl) piperazine-1-carboxylate (480 mg,2.42 mmol) and Pd (OH) 2/C (300 mg, 20%) in CH 3 OH (10 mL) was stirred at room temperature overnight under H 2 and 1 atm. The mixture was filtered through celite and the filtrate was concentrated to give the desired product (700 mg, crude) which was used in the next reaction without further purification.
Step 5 tert-butyl 4- (3- ((1 s,3 s) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) tert-butyl) oxy) cyclobutoxy) propyl) piperazine-1-carboxylate
To a solution of tert-butyl 4- (3- ((1 s,3 s) -3-hydroxycyclobutoxy) propyl) piperazine-1-carboxylate (180 mg,0.57 mmol) and 7- (6-fluoropyridin-3-yl) -5H-pyrido [4,3-b ] indole (100 mg,0.379 mmol) in NMP (10 mL) at room temperature was added NaH (60%, 100mg,2.5 mmol). The resulting solution was heated to 90 ℃ for 2 hours. After cooling to room temperature, the reaction was quenched with saturated solution of NH 4 Cl (20 mL) and the mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na 2SO4 and concentrated in vacuo. The residue was purified by preparative TLC using DCM/CH 3 OH (15:1) to give the desired product (120 mg,0.21 mmol) as a brown solid.
Step 6 7- (6- ((1 s,3 s) -3- (3- (piperazin-1-yl) propoxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole
A mixture of tert-butyl 4- (3- ((1 s,3 s) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) propyl) piperazine-1-carboxylate (120 mg,0.21 mmol) in a solution of CH 3 OH (2.0 mL) and HCl in 1, 4-dioxane (4.0 mL) was stirred at room temperature for 2 hours. The solvent was removed under vacuum to give the desired product (100 mg, crude) which was used in the next reaction without further purification.
Step 7 5- (4- (3- ((1 s,3 s) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) propyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
To a mixture of 7- (6- ((1 s,3 s) -3- (3- (piperazin-1-yl) propoxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole (80 mg, crude) and DIEA (300 mg,2.36 mmol) in NMP (2.0 mL) was added 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (100 mg,0.36 mmol). The mixture was heated by microwaves at 130 ℃ for 45 minutes. After cooling to room temperature, the reaction was taken up in EtOAc (100 mL). The mixture was washed with brine (20 ml x 3). The organic phase was dried over Na 2SO4 and concentrated in vacuo. The residue was purified by preparative TLC using DCM/CH 3OH/NH3H2 O (15:1:0.1) to give the title product as a yellow solid (16.0 mg, 13%).
1H NMR(400MHz,CDCl3):δ9.34(s,1H),8.55(d,J＝5.6Hz,1H),8.44(m,2H),8.20(d,J＝8.4Hz,1H),7.87-7.92(m,3H),7.68(d,J＝8.4Hz,1H),7.60(s,1H),7.48-7.50(m,1H),7.38(d,J＝5.6Hz,1H),7.06(m,1H),6.84(d,J＝8.8Hz,2H),4.93-4.94(m,2H),3.75(m,2H),3.42-3.49(m,6H),2.72-2.98(m,5H),2.61(s,4H),2.53(t,J＝7.2Hz,2H),2.15-2.18(m,2H),1.81(t,J＝6.8Hz,2H).(M+H)+ 714.3
Synthetic scheme for exemplary Compound 55
Step 1 t-butyl I-4- (5- (3-methoxy-3-oxoprop-1-en-1-yl) pyridin-2-yl) piperazine-1-carboxylate
To a solution of tert-butyl 4- (5-formylpyridin-2-yl) piperazine-1-carboxylate (1.0 g,3.44 mmol) and methyl 2- (dimethoxyphosphoryl) acetate (750 mg,4.12 mmol) in THF (15 ml) was added DBU (1.57 g,10.3 mmol). The reaction mixture was stirred at room temperature overnight. After it was quenched with water H 2 O (10 mL), the mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with brine and dried over Na 2SO4. It was filtered and concentrated under vacuum. The residue was crushed with petroleum ether to give the desired product as an off-white solid (800 mg,2.3mmol, yield: 66.9%).
Step2 t-butyl 4- (5- (3-hydroxypropyl) pyridin-2-yl) piperazine-1-carboxylate
To tert-butyl I-4- (5- (3-methoxy-3-oxoprop-1-en-1-yl) pyridin-2-yl) piperazine-1-carboxylic acid ester
To a solution of (800 mg,2.3 mmol) CH 3 OH (8 mL) and THF (35 mL) was added NaBH 4 (874 mg,23.0 mmol). The mixture was heated to 80 ℃ for a total of 3 hours. After cooling to room temperature, the reaction was quenched with 2N NH 4 Cl and the mixture was extracted with EtOAc (80 mL X3). The combined organic layers were washed with brine and dried (Na 2SO4), filtered and concentrated under reduced pressure. The residue was purified by a silica gel column (EA: pe=1:1) to give the desired compound (420 mg,1.31mmol, yield: 57.0%) as a yellow oil.
Step 3 tert-butyl 4- (5- (3- ((methylsulfonyl) oxy) propyl) pyridin-2-yl) piperazine-1-carboxylate
To a solution of tert-butyl 4- (5- (3-hydroxypropyl) pyridin-2-yl) piperazine-1-carboxylate (50 mg,0.16 mmol) and Et 3 N (48 mg,0.48 mmol) in DCM (2 mL) was added MsCl (27 mg,0.23 mmol). The reaction was stirred at room temperature for 1 hour. After it was quenched with water H 2 O (30 mL), the mixture was extracted with DCM (20 mL). The organic phase was washed with brine, dried over Na 2SO4, filtered and concentrated in vacuo to give the crude desired compound (64 mg) as a yellow oil, which was used in the next reaction without further purification.
Step4 tert-butyl 4- (5- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) propyl) pyridin-2-yl) piperazine-1-carboxylate
To a solution of tert-butyl 4- (5- (3- ((methylsulfonyl) oxy) propyl) pyridin-2-yl) piperazine-1-carboxylate (64 mg,0.16 mmol) and 2- (2, 6-dioxopiperidin-3-yl) -5-hydroxyisoindoline-1, 3-dione (66 mg,0.24 mmol) in DMF (5 ML) was added K 2CO3 (55 mg,0.40 mmol). The reaction mixture was stirred at 90 ℃ for 2 hours. After cooling to room temperature, the reaction was quenched with water (5 mL) and the mixture was extracted with dichloromethane (30 mL). The organic phase was washed with water and brine, dried over Na 2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (MeOH: dcm=1:100-1:20) to give the title product (30 mg,0.052mmol, yield: 32%).
Step 5 2- (2, 6-Dioxopiperidin-3-yl) -5- (3- (6- (piperazin-1-yl) pyridin-3-yl) propoxy) isoindoline-1, 3-dione
To a solution of tert-butyl 4- (5- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) propyl) pyridin-2-yl) piperazine-1-carboxylate (200 mg,0.39 mmol) in dioxane (10 mL) was added a solution of 6N HCl in dioxane (2 mL,12.0 mmol). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to give the crude title product (200 mg) as a yellow solid.
Step 6 (6- (3-hydroxy-prop-1-yn-1-yl) pyridin-3-yl) boronic acid
To a solution of (6-bromopyridin-3-yl) boronic acid (1.0 g,4.95 mmol) and prop-2-yn-1-ol (830 mg,14.8 mmol) in THF (30 mL) were added PdCl 2(PPh3)2(350mg,0.50mmol)、iPr2 NH (2 g,19.8 mmol) and CuI (95 mg,0.5 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was filtered through celite, and 1N NaOH (10 mL) was added to the filtrate. The mixture was extracted with DCM. The pH was adjusted to about 6 with 2N HCl. The aqueous solution was extracted with ethyl acetate. The combined EtOAc layers were dried over Na 2SO4, filtered, and evaporated to dryness under reduced pressure to give the desired compound as an off-white solid (500 mg,2.82mmol, 57% yield).
Step 7 3- (5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) prop-2-yn-1-ol
To a mixture of 7-bromo-5H-pyrido [4,3-b ] indole (50 mg,0.20 mmol) and (6- (3-hydroxyprop-1-yn-1-yl) pyridin-3-yl) boronic acid (53 mg,0.30 mmol) in dioxane (10 mL) and water (1.0 mL) was added PdCl 2(dppf)(29mg,0.04mmol)、Cs2CO3 (130 mg,0.40 mmol) and tBu3PHBF4 (23 mg,0.08 mmol). The mixture was stirred at 100 ℃ for 3 hours under N 2 atmosphere. After cooling to room temperature, the reaction was quenched with water (3 mL) and the mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried (Na 2SO4), filtered and concentrated under reduced pressure. The residue was purified on a silica gel column (MeOH: dcm=1:20-1:10) to give the desired compound as a yellow solid (30 mg,0.10mmol, yield: 50.0%).
Step 8 3- (5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) propan-1-ol
To a solution of 3- (5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) propan-2-yn-1-ol (30 mg,0.10 mmol) in MeOH (2 mL) was added Pd (OH) 2/C (20%, 10 mg) and saturated concentrated HCl (0.1 mL). The reaction was stirred at room temperature for 2 hours under H 2 atmosphere. The mixture was filtered through celite, and the filtrate was concentrated to give the crude desired compound (30 mg) as a yellow oil.
Step 9 3- (5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) propanal
A solution of 3- (5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) propan-1-ol (100 mg,0.33 mmol) in DMSO (4 mL) was mixed with IBX (231 mg,0.82 mmol). The reaction mixture was stirred at 25 ℃ for 2 hours. The reaction was quenched with saturated Na 2S2O3 (2 mL) and saturated NaHCO 3 (2 mL). The mixture was extracted with dichloromethane (30 mL). The organic phase was washed with water and brine. It was dried over Na 2SO4, filtered, and concentrated under reduced pressure to give the crude title product (60 mg) as a yellow oil.
Step 10 5- (3- (6- (4- (3- (5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) propyl) piperazin-1-yl) pyridin-3-yl) propoxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
To a solution of 3- (5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) propanal (100 mg, crude) in MeOH (10 mL) was added 2- (2, 6-dioxopiperidin-3-yl) -5- (3- (6- (piperazin-1-yl) pyridin-3-yl) propoxy) isoindoline-1, 3-dione (100 mg,0.21 mmol) and NaBH 3 CN (41 mg,0.66 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (6 ml) and extracted with DCM (20 ml x 2). The combined organic layers were washed with water and brine, dried over Na 2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the desired product (15 mg,0.02 mmol) as a white solid.
1H NMR(400MHz,MeOD):δ9.62(s,1H),9.03(s,1H),8.58(d,J＝6.8Hz,1H),8.52(d,J＝8.0Hz,1H),8.31-8.40(m,1H),8.08(s,1H),7.87-7.99(m,2H),7.78-7.87(m,3H),7.68-7.72(m,1H),7.26-7.30(m,2H),7.10-7.14(m,1H),5.08-5.12(m,1H),4.17(t,J＝6.0Hz,2H),3.81-3.92(m,4H),3.50-3.60(m,4H),3.30-3.40(m,2H),3.10-3.18(m,2H),2.71-2.86(m,5H),2.30-2.33(m,2H),2.10-2.16(m,3H).(M+H)+ 763.3
Synthetic scheme for exemplary Compound 56
5- ((5- (4- (2- ((1 S,3 s) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) ethyl) piperazin-1-yl) pentyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
Step 1 (1 s,3 s) -3- (benzyloxy) cyclobutan-1-ol
To a solution of 3- (benzyloxy) cyclobutanone (10.0 g,56.75 mmol) in EtOH (100 mL) at 0deg.C was added NaBH 4 (4.3 g,68.1 mmol). The mixture was stirred at 10 ℃ for 2 hours. After quenching the reaction with 10% NH 4 Cl, the mixture was extracted with ethyl acetate (200 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude desired product (9.5 g) as a colourless oil, which was used in the next step without further purification.
Step 2(((1 s,3 s) -3- (2, 2-diethoxyethoxy) cyclobutoxy) methyl) benzene
To a solution of (1 s,3 s) -3- (benzyloxy) cyclobutan-1-ol (300 mg, crude, 1.69 mmol) in THF (10 mL) was added NaH (168 mg,4.22mmol, 60%). After stirring at 5℃for 0.5h, 2-bromo-1, 1-diethoxyethane (333 mg,3.38 mmol) was added. The resulting mixture was stirred at 70 ℃ for 18 hours. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and the mixture was extracted with EA. The organic phase was washed with brine, dried over MgSO 4 and concentrated. The residue was purified by chromatography (silica gel, PE: EA (50:1, v: v)) to give the desired compound (220 mg) as a yellow solid.
Step 3:2- ((1 s,3 s) -3- (benzyloxy) cyclobutoxy) acetaldehyde
To a solution of (((1 s,3 s) -3- (2, 2-diethoxyethoxy) cyclobutoxy) methyl) benzene (220 mg,0.74 mmol) in CH 3 CN (5 mL) was added HCl (2 mL, 2.5mol/L in H 2 O). The resulting mixture was stirred at 70 ℃ for 2 hours. TLC (PE: ea=3:1, rf=0.5) showed that starting material was consumed. The mixture was diluted with water (50 mL) and extracted with EA. The organic phase was washed with NaHCO 3, brine. The solution was dried over MgSO 4 and concentrated to give the desired compound (170 mg, crude) as a yellow oil, which was used in the next step without further purification.
Step 4 t-butyl 4- (2- ((1 s,3 s) -3- (benzyloxy) cyclobutoxy) ethyl) piperazine-1-carboxylate
To a solution of 2- ((1 s,3 s) -3- (benzyloxy) cyclobutoxy) acetaldehyde (170 mg, crude, 0.772 mmol) in MeOH (10 mL) was added tert-butylpiperazine-1-carboxylate (215 mg,1.16 mmol), acOH (1 drop), and NaBH 3 CN (97 mg,154 mmol). The resulting mixture was stirred at 10 ℃ for 18 hours. The reaction mixture was diluted with water (50 mL) and the mixture extracted with EA. The organic phase was washed with brine, dried over MgSO 4 and concentrated. The residue was purified by chromatography (silica gel, PE: EA (1:1, v: v)) to give the desired compound (280 mg) as a colorless oil.
Tert-butyl 4- (2- ((1 s,3 s) -3- (benzyloxy) cyclobutoxy) ethyl) piperazine-1-carboxylate was converted to the title compound, 5- ((5- (4- (2- ((1 s,3 s) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) ethyl) piperazine-1-yl) pentyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione, according to the procedure described above for exemplary compound 42 and exemplary compound 53, following the protocol below.
Exemplary Compounds 56：1H NMR(400MHz,CDCl3)δ9.33(s,1H),8.89(s,1H),8.53(s,1H),8.42(s,1H),8.18(d,J＝8.2Hz,1H),7.87(d,J＝6.2Hz,1H),7.77(d,J＝8.2Hz,1H),7.62(s,1H),7.49(d,J＝7.7Hz,1H),7.42(s,1H),7.29(d,J＝11.5Hz,1H),7.17(d,J＝6.5Hz,1H),6.82(d,J＝8.2Hz,1H),5.34(s,2H),5.00–4.87(m,1H),4.07(s,2H),3.75(s,1H),3.57(s,1H),3.04–2.49(m,10H),2.20(m,4H),2.01(s,4H),1.85(s,3H),1.75–1.55(m,3H),1.52(s,2H).
Exemplary compound 54 and exemplary compound 58 were prepared according to the schemes below and using procedures similar to those described above.
Synthetic scheme for exemplary Compound 57
Step 1 benzyl 4- (5H-pyrido [4,3-b ] indol-7-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid ester
A mixture of 7-bromo-5H-pyrido [4,3-b ] indole (492 mg,2 mmol), benzyl 4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (755mg, 2.2 mmol), pd (am phose) Cl 2 (146 mg,0.2 mmol) and CsF (1.2 g,8 mmol) in dioxane/H 2 O (20 mL/2 mL) was stirred at 90℃for 16H. After cooling to room temperature, the reaction was quenched by the addition of water (30 mL). The mixture was extracted with ethyl acetate (20 ml x 3). The combined organic layers were washed with brine (20 ml x 2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with methylene chloride/methanol to give 260mg (0.68 mmol, 34%) of the desired product.
Step 2 7- (piperidin-4-yl) -5H-pyrido [4,3-b ] indole
To benzyl 4- (5H-pyrido [4,3-b ] indol-7-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (130 mg,0.34 mmol) and one drop of concentrated HCl in CH 3 OH (10 mL) at room temperature was added Pd/C (13 mg, 10%). The resulting solution was stirred at room temperature overnight under 1atm of H 2. The solid was then filtered off and the filtrate concentrated in vacuo to give the crude product (80 mg) which was used in the next reaction without further purification.
Step 3 5- ((14- (4- (5H-pyrido [4,3-b ] indol-7-yl) piperidin-1-yl) -3,6,9, 12-tetraoxatetradecyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
To a solution of 7- (piperidin-4-yl) -5H-pyrido [4,3-b ] indole (80 mg,0.32 mmol) and 14- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) -3,6,9, 12-tetraoxapentadecanol (175 mg,0.36 mmol) [ prepared as described for intermediate 101 above ] in CH 3 OH (10 mL) was added NaBH 3 CN (40 mg,0.64 mmol) and a drop of CH 3 COOH at room temperature. After stirring for 2 hours, the reaction was quenched by the addition of water (20 mL). The resulting solution was extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 ml x 2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC using DCM/CH 3 OH (10:1) to give the desired product (18mg,0.025mmol,8％).1H NMR(400MHz,CD3OD):δ9.30(s,1H),8.42-8.60(m,2H),8.19(d,J＝8.0Hz,1H),7.60-7.65(m,2H),7.52(s,1H),7.31(d,J＝8.0Hz,1H),7.19(s,1H),7.12-7.14(m,1H),5.07-5.10(m,1H),4.12(t,J＝4.0Hz,2H),3.66-3.86(m,18H),3.37(s,2H),3.15-3.20(m,3H),2.71-2.76(m,3H),2.09-2.22(m,5H).(M+H)+ 728.3.
Synthetic scheme for exemplary Compound 60
5- (4- (3- ((1 R,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) propyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
Step 1 t-butyl 4- (3- ((1 r,3 r) -3- ((4-nitrobenzoyl) oxy) cyclobutoxy) propyl) piperazine-1-carboxylate
To a solution of tert-butyl 4- (3- ((1 s,3 s) -3-hydroxycyclobutoxy) propyl) piperazine-1-carboxylate (530 mg,1.68 mmol), triphenylphosphine (1.32 g,5.06 mmol) and 4-nitrobenzoic acid (310 mg,1.85 mmol) in THF (10 mL) at room temperature was added dropwise DIAD (1.02 g,5.06 mmol) under N 2. After stirring at room temperature for 3 hours, it was quenched with water (20 mL) and the mixture extracted with EtOAc (20 mL x 2). The combined organic layers were concentrated in vacuo. The residue was purified by a silica gel column with PE/EA from 2:1 to 1:1 as eluent to give the desired product as a semi-solid (350 mg, 45%).
Tert-butyl 4- (3- ((1 r,3 r) -3- ((4-nitrobenzoyl) oxy) cyclobutoxy) propyl) piperazine-1-carboxylate was converted to the title compound, 5- (4- (3- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) propyl) piperazine-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione according to the protocol described below and using the procedure described above for exemplary compound 53.
Compounds of formula (I) 60：1H NMR(400MHz,DMSO-d6):δ11.07(s,1H),9.76(s,1H),8.67(d,J＝6.0Hz,1H),8.60(s,1H),8.52(d,J＝8.4Hz,1H),8.16(d,J＝8.4Hz,1H),8.80-8.02(m,2H),7.77(t,J＝8.4Hz,2H),7.50(s,1H),7.37(d,J＝8.0Hz,1H),6.96(d,J＝8.8Hz,1H),5.36(m,1H),5.07-5.11(m,1H),4.24(br,3H),3.62(br,9H),3.55(s,3H),3.17-.3.25(m,6H),2.86-2.93(m,1H),2.38-2.62(m,4H),1.97-2.04(m,1H).(M+H)+ 714.3.
Synthetic scheme for exemplary Compound 61
2- (2, 6-Dioxopiperidin-3-yl) -5- ((5- (4- (3- (5- (5- (2, 2-trifluoroethyl) -5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) propyl) piperazin-1-yl) pentyl) oxy) isoindoline-1, 3-dione
Step 1 7- (6- (3- ((tert-butyldimethylsilyl) oxy) propyl) pyridin-3-yl) -5H-pyrido [4,3-b ] indole
To a solution of 3- (5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) propan-1-ol (prepared as described for compound 55; 100mg,0.33 mmol) in DCM (5 mL) was added imidazole (44.8 mg,0.66 mmol) and TBSCl (59.6 mg,0.40 mmol). The resulting solution was stirred at 40 ℃ for 3 hours. The solvent was removed under reduced pressure. The residue was diluted with EA (30 mL) and the mixture was washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/meoh=20/1, 0.2% net 3) to give the title product (100 mg,73% yield).
Step 2 7- (6- (3- ((tert-Butyldimethylsilyl) oxy) propyl) pyridin-3-yl) -5- (2, 2-trifluoroethyl) -5H-pyrido [4,3] -b ] indole
To a solution of 7- (6- (3- ((tert-butyldimethylsilyl) oxy) propyl) pyridin-3-yl) -5H-pyrido [4,3-b ] indole (60 mg,0.14 mmol) in DMF (5 mL) at 5℃was added NaH (8.6 mg,0.22 mmol). After stirring for 20min, a solution of CF 3CH2 Otf (66.6 mg,0.29 mmol) in DMF (1 mL) was added dropwise. The mixture was stirred for an additional 1 hour and the reaction was diluted with EtOAc (40 mL), washed with brine and dried over anhydrous sodium sulfate. The filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM/meoh=40:1, 0.2% nh 3·H2 O) to give the title product (55 mg, 92%).
Step 3- (5- (5- (2, 2-trifluoroethyl) -5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) propan-1-ol
To a solution of 7- (6- (3- ((tert-butyldimethylsilyl) oxy) propyl) pyridin-3-yl) -5- (2, 2-trifluoroethyl) -5H-pyrido [4,3-b ] indole (110 mg,0.22 mmol) in CH 3 OH (2 mL) was added HCl/dioxane (6N, 3 mL). The resulting solution was stirred at 5 ℃ for 1 hour. It was then diluted with EtOAc (40 mL) and the mixture was washed with saturated NaHCO 3 (aqueous) and brine, and dried over anhydrous sodium sulfate. The organic phase was evaporated under reduced pressure to give the crude title product (84.9 mg) which was used in the next reaction without further purification.
Step 4 3- (5- (5- (2, 2-trifluoroethyl) -5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) propanal
To a solution of 3- (5- (5- (2, 2-trifluoroethyl) -5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) propan-1-ol (90 mg,0.23 mmol) in DMSO (2 mL) was added IBX (130.9 mg,0.47 mL). The resulting mixture was stirred at 40 ℃ for 2 hours. The mixture was quenched with saturated aqueous Na 2S2O3 mL and saturated aqueous NaHCO 3 (5 mL). The mixture was extracted with EtOAc (20 ml x 5). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude desired product (89.5 mg) which was used in the next reaction without further purification.
Step 5 tert-butyl 4- (5- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) pentyl) piperazine-1-carboxylate
To a solution of 5- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) valeraldehyde (150 mg,0.42 mmol) [ prepared according to the procedure above ] in MeOH (5 mL) was added tert-butylpiperazine-1-carboxylate (77.9 mg,0.42 mmol) and NaBH 3 CN (52.6 mg,0.84 mmol). The resulting solution was stirred at 40 ℃ for 2 hours. The solvent was evaporated under reduced pressure. The residue was diluted with EA (30 mL), and the mixture was washed with brine. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/meoh=60/1) to give the desired product (200 mg,90% yield).
The compounds of steps 4 and 5 were converted to the final compound, 2- (2, 6-dioxopiperidin-3-yl) -5- ((5- (4- (3- (5- (2, 2-trifluoroethyl) -5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) propyl) piperazin-1-yl) pentyl) oxy) isoindoline-1, 3-dione using BOC-deprotection and reductive amination procedures similar to those described above.
1H NMR(400MHz,CD3OD)δ9.35(s,1H),8.89(s,1H),8.55(d,J＝5.8Hz,1H),8.40(d,J＝8.0Hz,1H),8.17–8.22(m,1H),8.05(s,1H),7.81(d,J＝8.3Hz,1H),7.74(d,J＝5.6Hz,1H),7.51(d,J＝8.2Hz,1H),7.40(s,1H),7.33(s,1H),5.40(d,J＝9.1Hz,2H),5.08–5.16(m,1H),4.95(s,4H),4.59(s,2H),4.18(t,J＝6.2Hz,1H),2.91–3.00(m,2H),2.58–2.91(m,9H),2.12–2.18(m,1H),2.06(s,2H),1.89(s,2H),1.69(s,2H),1.57(s,2H).(M+H)+ 796.3.
Synthetic scheme for exemplary Compound 62
3- (5- ((5- (4- (3- (5- (5-Methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) propyl) piperazin-1-yl) pentyl) oxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione
Step 1 t-butyl 5-amino-4- (5- ((5-hydroxypentyl) oxy) -1-oxoisoindolin-2-yl) -5-oxopentanoate
To a solution of tert-butyl 5-amino-4- (5-hydroxy-1-oxoisoindolin-2-yl) -5-oxopentanoate (500.0 mg,1.0 eq), pentane-1, 5-diol (187 mg,1.2 eq) and PPh3 (590.0 mg,1.5 eq) in dry tetrahydrofuran (50 mL) was added DIAD (4575 mg,2.25mmol,1.5 eq). The resulting solution was stirred at room temperature for 16 hours. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (50 ml x 3). The combined organic layers were washed with brine (20 ml x 2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with dichloromethane/methanol (10:1) to give the desired product (560 mg,1.33mmol, 89%).
Step 23- (5- ((5-hydroxypentyl) oxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione
To a solution of tert-butyl 5-amino-4- (5- ((5-hydroxypentyl) oxy) -1-oxoisoindolin-2-yl) -5-oxopentanoate (560 mg,1.0 eq) in MeCN (20 mL) at room temperature was added p-TsA (255 mg,3.0 eq). The resulting solution was stirred at 90 ℃ for 6 hours. The reaction was then cooled to room temperature and quenched by the addition of water (10 mL). The resulting solution was extracted with ethyl acetate (15 ml x 3). The combined organic layers were washed with brine (10 ml x 2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with dichloromethane/methanol (10:1) to give the desired product (190 mg,0.55mmol, 46%).
Step 35- ((2- (2, 6-Dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) oxy) valeraldehyde
To a solution of 3- (5- ((5-hydroxypentyloxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (190 mg,1.0 eq) in DCM (20 mL) at room temperature was added IBX (100 mg,2 eq). The resulting solution was stirred at room temperature for 2 hours. The solid was then filtered off and the filtrate concentrated in vacuo to give the crude product (190 mg) which was used in the next reaction without further purification.
Step 4 7-bromo-5-methyl-5H-pyrido [4,3-b ] indole ]
To a solution of 7-bromo-5H-pyrido [4,3-b ] indole (8.0 g,32.4 mmol) in N, N-dimethylformamide (50 ml) at 0℃was added sodium hydride (1.4 g,35.6mmol, 60% in mineral oil) and the reaction mixture was stirred at 0℃for 30 min. Methyl iodide (4.6 g,32.4 mmol) was added to the resulting mixture at 0 ℃, and the reaction mixture was allowed to warm to room temperature and stirred overnight. TLC showed the reaction was complete. The reaction mixture was quenched with water (30 ml) at 0 ℃ and extracted with ethyl acetate (50 ml x 2). The combined organic layers were washed with water (80 ml) followed by brine (90 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by general silica gel flash chromatography (eluting with 20-40% ethyl acetate in hexane) to give 7-bromo-5-methyl-5H-pyrido [4,3-b ] indole (6.0 g, 71% yield) as a brown solid.
According to the scheme below, 5- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) oxy) valeraldehyde was converted to the title compound, 3- (5- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) propyl) piperazin-1-yl) pentyl) oxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione using the procedure described above for exemplary compound 61.
Exemplary Compounds 62：1HNMR(400MHz,MeOD):δ9.27(s,1H),8.86(d,J＝2.0Hz,1H),8.46(d,J＝6.0Hz,1H),8.33(d,J＝8.0Hz,1H),8.16(d,J＝2.4Hz,1H),7.90(s,1H),7.59-7.70(m,3H),7.47(d,J＝6.0Hz,1H),7.03-7.09(m,2H),5.06-5.12(m,1H),4.42(d,J＝5.6Hz,2H),4.07(t,J＝6.4Hz,2H),3.99(s,3H),2.89-2.96(m,3H),2.51-2.75(m,13H),2.12-2.24(m,1H),2.01-2.03(m,3H),1.82-1.84(m,2H),1.52-1.63(m,6H).(M+H)+ 714.3.
Exemplary Compound 63
2- (2, 6-Dioxopiperidin-3-yl) -5- ((5- (4- (3- (5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) -3- (trifluoromethyl) pyridin-2-yl) propyl) piperazin-1-yl) pentyl) oxy) isoindoline-1, 3-dione
Step 1 5-methyl-7- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -5H-pyrido [4,3-b ] indole
To a solution of 7-bromo-5-methyl-5H-pyrido [4,3-b ] indole (150 mg,0.577 mmol) in dioxane was then added KOAc (114 mg,1.15 mmol), pd (dppf) Cl 2 (35 mg,0.05 mmol) and 4,4', 5' -octamethyl-2, 2' -bis (1, 3, 2-dioxaborane) (254 mg,1.15 mmol). The resulting solution was heated to 100 ℃ overnight under N 2. After cooling to room temperature, the reaction was quenched with water and the mixture was extracted with EtOAc (10 ml x 2). The combined organic layers were washed with brine (10 mL). The organic phase was dried over Na 2SO4 and concentrated in vacuo to give the crude desired product (180 mg, crude) which was used in the next reaction without further purification.
Step 2 7- (6-chloro-5- (trifluoromethyl) pyridin-3-yl) -5-methyl-5H-pyrido [4,3-b ] indole
To a mixture of 5-bromo-2-chloro-3-trifluoromethylpyridine (135 mg,0.7 mmol) and 5-methyl-7- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2- (yl) -5H-pyrido [4,3-b ] indole (180 mg,0.58 mmol) in dioxane/H 2 O (v/v=10/1, 10 mL) was added Pd (dppf) 2Cl2 (20 mg, 10%) and CsF (180 mg,1.16 mmol) the mixture was stirred at 80 ℃ overnight, the solution was quenched with water, the mixture was extracted with ethyl acetate (20 mL), and the combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.
Step 3 tert-butyl 4- (3- (5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) -3- (trifluoromethyl) pyridin-2-yl) tert-butyl) prop-2-yn-1-yl) piperazine-1-carboxylate
To a mixture of 7- (6-chloro-5- (trifluoromethyl) pyridin-3-yl) -5-methyl-5H-pyrido [4,3-b ] indole (170 mg,0.58 mmol) and tert-butyl 4- (prop-2-ynyl) piperazine-1-carboxylate (156 mg,0.69 mmol) in DMF (10 mL) was added Pd(PPh3)2Cl2(17mg,10％)、Cs2CO3(378mg,1.16mmol)、DBU(30mg,0.116mmol) and t-Bu 3 P (25 mg,0.116 mmol). The mixture was heated by microwaves at 150 ℃ for 10 minutes. The reaction mixture was quenched with water. The mixture was extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the desired product (200 mg).
Step 4 tert-butyl 4- (3- (5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) -3- (trifluoromethyl) pyridin-2-yl) propyl) piperazine-1-carboxylate
To an ethanol solution of tert-butyl 4- (3- (5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) -3- (trifluoromethyl) pyridin-2-yl) prop-2-yn-1-yl) piperazine-1-carboxylate (200 mg) was added Pd/C (20 mg). The mixture was stirred at 30℃under H 2 atmosphere (3 MPa) for 8 hours. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC to give the desired product (25 mg).
Tert-butyl 4- (3- (5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) -3- (trifluoromethyl) pyridin-2-yl) propyl) piperazine-1-carboxylate was converted to the title compound, 2- (2, 6-dioxopiperidin-3-yl) -5- ((5- (4- (3- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) -3- (trifluoromethyl) pyridin-2-yl) propyl) piperazin-1-yl) pentyl) oxy) isoindoline-1, 3-dione, using the BOC-deprotection and reductive amination procedure described above according to the following scheme.
Exemplary Compounds 63：1H NMR(400MHz,CD3OD):δ9.25(s,1H),8.45(s,1H),8.23(d,J＝7.6Hz,1H),7.76(d,J＝8.4Hz,1H),7.66(s,1H),7.59(d,J＝8.0Hz,1H),7.39(d,J＝8.4Hz,1H),7.35(s,2H),7.26-7.28(m,1H),6.06(s,1H),5.72(s,1H),5.06–5.08(m,1H),4.30(d,J＝6.4Hz,1H),4.11–4.15(m,2H),3.90–3.94(m,4H),3.70–3.74(m,2H),3.03–3.06(m,2H),2.82–2.88(m,4H),2.71–2.75(m,6H),2.51–2.55(m,3H),2.05–2.25(m,2H),1.82–1.86(m,2H),1.61–1.63(m,2H),1.51–1.52(m,2H).(M+H)+ 796.2.
Exemplary Compound 73
Step 1 7- (6- ((1 s,3 s) -3- (benzyloxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole
To a solution of 7- (6-fluoropyridin-3-yl) -5H-pyrido [4,3-b ] indole (1.1 g,4.18 mmol) and (1 s,3 s) -3- (benzyloxy) cyclobutanol (745 mg,4.18 mmol) in 1-methylpyrrolidin-2-one (2 ml) at 0℃was added sodium hydride (60% in mineral oil) (334 mg,8.35 mmol). The mixture was stirred at room temperature for 2 hours. TLC showed the reaction was complete. The mixture was partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer was collected, washed with brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluting with 2-5% methanol in dichloromethane) to give 7- (6- ((1 s,3 s) -3- (benzyloxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole (1.42 g, 82%) as a white solid.
Step2 (1 s,3 s) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutan-1-ol
A mixture of 7- (6- ((1 s,3 s) -3- (benzyloxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole (1.42 g,3.37 mmol) and palladium on carbon (10%, 150 mg) in methanol (30 ml) -tetrahydrofuran (10 ml) was stirred at 50℃for 2 hours under hydrogen atmosphere (hydrogen balloon). TLC showed the reaction was complete. Palladium on carbon was removed by filtration and washed with methanol (10 ml x 2). The combined filtrates were concentrated under reduced pressure to give (1 s,3 s) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutanol (1.57 g, crude) as a white solid.
Step 3 tert-butyl 7- (6- ((1 s,3 s) -3-hydroxycyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole-5-carboxylic acid ester
To a suspension of (1 s,3 s) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutanol (1.57 g,4.27 mmol) and sodium carbonate (1.1 g,10.69 mmol) in tetrahydrofuran (20 ml) -water (5 ml) was added di-tert-butyl carbonate (1.2 g,5.55 mmol) at room temperature. The mixture was stirred at room temperature for 17 hours. TLC showed the reaction was complete. The mixture was concentrated, and the residue was partitioned between ethyl acetate (20 ml) and water (30 ml). The organic layer was collected, washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluting with 1-2% methanol in dichloromethane) to give tert-butyl 7- (6- ((1 s,3 s) -3-hydroxycyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole-5-carboxylate (1.1 g, 73%) as a white solid.
Step 4 tert-butyl 7- (6- ((1 s,3 s) -3- ((methylsulfonyl) oxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole-5-carboxylate
To a suspension of tert-butyl 7- (6- ((1 s,3 s) -3-hydroxycyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole-5-carboxylate (500 mg,1.16 mmol) and triethylamine (352 mg,3.47 mmol) in dichloromethane (10 ml) was added methanesulfonyl chloride (530 mg,4.63 mmol) at 0 ℃. The resulting mixture was allowed to warm to room temperature and stirred at room temperature for 5 hours. TLC showed the reaction was complete. The mixture was diluted with dichloromethane (10 ml) and washed with water (10 ml). The organic layer was washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give tert-butyl 7- (6- ((1 s,3 s) -3-hydroxycyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole-5-carboxylate (700 mg, crude), which was used in the next step without further purification.
Step 5 7- (6- ((1 r,3 r) -3- ((6-iodopyridin-3-yl) oxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole
A mixture of tert-butyl 7- (6- ((1 s,3 s) -3-hydroxycyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole-5-carboxylic acid tert-butyl ester (350 mg,0.69 mmol), 6-iodopyridin-3-ol (155 mg,0.69 mmol) and cesium carbonate (452 mg,1.39 mmol) in anhydrous N, N-dimethylformamide (4 ml) was stirred at 90℃for 12 hours. TLC showed the reaction was complete. The mixture was partitioned between ethyl acetate (30 ml) and water (40 ml). The organic layer was collected, washed with brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluting with 1-2% methanol in dichloromethane) to give 7- (6- ((1 r,3 r) -3- ((6-iodopyridin-3-yl) oxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole (250 mg, 68%) as a pale yellow solid.
Step 6 [5- ((3- (5- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) prop-2-yn-1-yl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione ]
To a stirred solution of 7- (6- ((1 r,3 r) -3- ((6-iodopyridin-3-yl) oxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole (150 mg,0.24 mmol), 2- (2, 6-dioxopiperidin-3-yl) -5- (prop-2-yn-1-yloxy) isoindoline-1, 3-dione (111 mg,0.35 mmol) [ prepared using the procedure from step 1 of exemplary compound 180 ] and triethylamine (121 mg,1.20 mmol) in N, N-dimethylformamide (2 ml) was added under nitrogen atmosphere at room temperature, the mixture was degassed three times with nitrogen with bis (triphenylphosphine) palladium (II) chloride (8 mg,0.01 mmol) and cuprous iodide (2 mg,0.01 mmol). The resulting mixture was stirred under nitrogen at 65 ℃ overnight. TLC showed the reaction was complete. The mixture was partitioned between water (30 ml) and ethyl acetate (30 ml). The organic layer was collected and washed with brine (30 ml x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue that was purified by flash column chromatography on silica gel (eluting with 2% methanol in dichloromethane) to give 5- ((3- (5- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yn-1-yl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (45 mg, 26% yield) as a white solid.
1H NMR(400MHz,DMSOd-6):δ2.04-2.07(m,1H),2.57-2.77(m,6H),2.86-2.93(m,1H),5.10-5.14(m,2H),5.32(s,2H),5.39-5.48(m,1H),6.97(d,J＝8.0Hz,1H),7.32-7.33(m,1H),7.46-7.58(m,5H),7.77(s,1H),7.90(d,J＝7.2Hz,1H),8.14(d,J＝7.2Hz,1H),8.25(s,1H),8.30(d,J＝7.6Hz,1H),8.43(s,1H),8.56(s,1H),9.36(s,1H),11.12(s,1H),11.82(s,1H).(M+H)+ 719.4.
Synthetic scheme for exemplary Compound 77
Step 1 tert-butyl 7- (6- ((1 r,3 r) -3- ((6- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) propyl) pyridin-3-yl) oxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole-5-carboxylate
To a solution of tert-butyl 7- (6- ((1 r,3 r) -3- ((6- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) prop-1-yn-1-yl) pyridin-3-yl) oxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole-5-carboxylate (15 mg) in MeOH was added Pd/C. The solution was stirred at 30℃for 2 hours under H 2 (2 MPa). The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by silica gel to give the desired product (6 mg).
Step 2 5- (3- (5- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) propoxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
A solution of tert-butyl 7- (6- ((1 r,3 r) -3- ((6- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) propyl) 207 pyridin-3-yl) oxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole-5-carboxylate (6 mg) in DCM/TFA (2 mL/1 mL) was stirred at room temperature for 4 hours. The solvent was removed under vacuum to give 5- (3- (5- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) propoxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (5.5 mg).
1H NMR(400MHz,CD3OD):δ9.56(s,1H),8.54–8.56(m,2H),8.45(d,J＝8.4Hz,1H),8.37(d,J＝2.4Hz,1H),8.13(d,J＝8.0Hz,1H),7.97(d,J＝8.0Hz,1H),7.88(d,J＝8.8Hz,2H),7.81(d,J＝8.4Hz,1H),7.79(s,1H),7.76–7.78(d,J＝8Hz,1H),7.29(s,1H),7.21(d,J＝8.0Hz,1H),6.98(d,J＝8.0Hz,1H),5.48–5.52(m,1H),5.32–5.34(m,1H),5.18–5.22(m,1H),5.06–5.10(m,1H),4.25–4.28(m,2H),3.21–3.23(m,3H),2.78–2.81(m,5H),2.67–2.70(m,2H),2.30–2.33(m,2H),2.17–2.19(m,1H),1.97–2.07(m,3H).(M+H)+ 723.5.
Synthetic scheme for exemplary Compound 94
Step 1 (1 r,3 r) -3- ((6- (5- ((triisopropylsilyl) oxy) pent-1-yn-1-yl) pyridin-3-yl) oxy) cyclobutan-1-ol
To a solution of (1 r,3 r) -3- ((6-bromopyridin-3-yl) oxy) cyclobutan-1-ol (530 mg,2.17 mmol) in anhydrous THF (10 mL) was added triisopropyl (pent-4-yn-1-yloxy) silane (616 mg,2.61 mmol), TEA (1.1 g,10.86 mmol), cuI (45 mg,0.24 mmol) and Pd (PPh 3)2Cl2 (110 mg,4.34 mmol) at 25 ℃ C.) the resulting solution was stirred at 45 ℃ C. For 16 hours the reaction was diluted with H 2 O (10 mL.) the resulting mixture was extracted with EtOAc (10 mL x 2.) the combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the desired product (1 r,3 r) -3- ((6- (5- ((triisopropylsilyl) oxy) pent-1-yl) pyridin-3-yloxy) cyclobutan-ol (600 mg) as a colorless oil.
Step 2 5-bromo-2- ((1 r,3 r) -3- ((6- (5- ((triisopropylsilyl) oxy) pent-1-yn-1-yl) pyridin-3-yl) oxy) cyclobutoxy) pyridine
To a solution of (1 r,3 r) -3- (((6- (5- ((triisopropylsilyl) oxy) pent-1-yn-1-yl) pyridin-3-yl) oxy) cyclobutan-1-ol (300 mg,0.74 mmol) in DMF (5 mL) at 0℃was added NaH (45 mg,1.11 mmol) the reaction was stirred at 0℃for 0.5H, and 5-bromo-2-fluoropyridine (144 mg,0.82 mmol) was added dropwise at 0℃the reaction was stirred at 20℃for 2H. Diluted with H 2 O (10 mL) solution the resulting mixture was extracted with EtOAc (10 mL x 2), the combined organic layers were dried over anhydrous sodium sulfate and concentrated the residue was purified with a silica gel column to give the desired product 5-bromo-2- ((1 r,3 r) -3- ((6- (5- ((triisopropylsilyl) oxy) pent-1-yn-1-yl) pyridin-3-yl) oxy) cyclobutoxy) pyridine (240 mg,58% yield) as a white solid.
Step 3 5-methyl-7- (6- ((1 r,3 r) -3- ((6- (5- ((triisopropylsilyl) oxy) pent-1-yn-1-yl) pyridin-3-yl) oxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole
To a solution of 5-bromo-2- ((1 r,3 r) -3- ((6- (5- ((triisopropylsilyl) oxy) pent-1-yn-1-yl) pyridin-3-yl) oxy) cyclobutoxy) pyridine (180 mg,0.32 mmol) in 1, 4-dioxane (5 mL) and H 2 O (1 mL) at 15℃was added 5-methyl-7- (6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridin-3-yl) -5H-pyrido [4,3-b ] indole (119 mg,0.39 mmol), csF (147 mg,0.96 mmol) and Pd (aMphos) Cl 2 (34 mg,0.06 mmol). The resulting mixture was stirred at 80 ℃ for 5 hours. The mixture was quenched with H 2 O (20 mL) and extracted with EtOAc (10 mL. Times.2). The combined organic layers were then washed with brine (20 ml x 2), dried over anhydrous sodium sulfate and concentrated. The residue was purified with silica gel column to give the desired product 5-methyl-7- (6- ((1 r,3 r) -3- ((6- (5- ((triisopropylsilyl) oxy) pent-1-yn-1-yl) pyridin-3-yl) oxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole (80 mg,38% yield).
Step 4 5- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) pent-4-yn-1-ol
To a solution of 5-methyl-7- (6- ((1 r,3 r) -3- ((6- (5- ((triisopropylsilyl) oxy) pent-1-yn-1-yl) pyridin-3-methyl) oxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole (90 mg,0.14 mmol) in anhydrous THF (10 mL) at 15 ℃ was added a 1M solution of TBAF in THF (1 mL,0.7 mmol). The mixture was stirred under a balloon of N 2 at 40 ℃ for 1 hour. The mixture was concentrated. The residue was purified by preparative TLC to give the desired product 5- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) pent-4-yn-1-ol as a white solid (30 mg,43% yield).
Step 5 2- (2, 6-Dioxopiperidin-3-yl) -5- ((5- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyridinyl) o [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) pent-4-yn-1-yl) oxy) isoindoline-1, 3-dione
To a solution of 5- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) pent-4-yn-1-ol (25 mg,0.05 mmol) in anhydrous THF (2 mL) at 15 ℃ was added 2- (2, 6-dioxopiperidin-3-yl) -5-hydroxyisoindoline-1, 3-dione (20 mg,0.07 mmol), PPh 3 (40 mg,0.14 mmol). DIAD (32 mg,0.14 mmol) was added to the mixture at N 2 Lower part(s) , At the position of 40 ℃. The resulting mixture was stirred at 40 ℃ for 0.5 hours. The mixture was cooled to 20 ℃ and quenched with H 2 O (10 mL), extracted with EtOAc (10 mL x 2). The combined organic layers were then washed with brine (20 ml x 5), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative TLC to give the desired product 2- (2, 6-dioxopiperidin-3-yl) -5- ((5- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) pent-4-yn-1-yl) oxy) isoindoline 1, 3-dione as a white solid (22 mg,58% yield).
1HNMR(400MHz,DMSO-d6):δ:11.04(s,1H),9.29(s,1H),8.58(d,J＝2.0Hz,1H),8.43(d,J＝5.6Hz,1H),8.25(d,J＝8.0Hz,1H),8.12-8.16(m,2H),7.92(s,1H),7.78(d,J＝7.6Hz,1H),7.56(d,J＝6.0Hz,2H),7.40(s,1H),7.33(d,J＝8.4Hz,2H),7.20-7.22(m,1H),6.92(d,J＝4.4Hz,1H),5.37(s,1H),5.01-5.37(m,2H),4.25(t,J＝6.0Hz,2H),3.89(s,3H),2.43-2.65(m,9H),1.98(t,J＝6.4Hz,3H).(M+H)+ 761.5.
Synthetic schemes for exemplary Compound 117
Step 1 5-methyl-7- (6- ((1 r,3 r) -3- ((6- (3- ((tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-1-yl) pyridin-3-yl) oxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole
A mixture of (1 s,3 s) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutylmethanesulfonate (480 mg,1.1 mmol) [ prepared using the procedure described in step 4 for exemplary compound 73 ], 6- (3- ((tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-1-yl) pyridin-3-ol (256 mg,1.1 mmol) and cesium carbonate (7195 mg,2.2 mmol) in N, N-dimethylformamide (15 ml) was stirred at 70 ℃ for 16 hours. TLC showed the reaction was complete. The reaction mixture was partitioned between water (20 ml) and ethyl acetate (40 ml). The organic layer was collected, washed with brine (50 ml), dried over sodium sulfate and evaporated under reduced pressure to give a crude residue which was purified by flash column chromatography on silica gel (eluting with 0-30% ethyl acetate in hexane) to give 5-methyl-7- (6- ((1 r,3 r) -3- ((6- (3- ((tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-1-yl) pyridin-3-yl) oxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole (350 mg, 57%) as a white solid.
Step 2 3- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) prop-2-yn-1-ol
To a solution of 5-methyl-7- (6- ((1 r,3 r) -3- ((6- (3- ((tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-1-yl) pyridin-3-yloxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole (350 mg,0.62 mmol) in tetrahydrofuran (10 ml) was added aqueous hydrogen chloride (5 ml,2 m) and the reaction mixture stirred at room temperature for 1 hour. TLC showed the reaction was complete. The reaction mixture was quenched with aqueous sodium bicarbonate (20 ml), and the reaction mixture was extracted with ethyl acetate (20 ml). The organic layer was collected and the aqueous layer was extracted with ethyl acetate (10 ml x 2). The combined organic layers were washed with brine (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 3- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) prop-2-yn-1-ol (270 mg, crude) as a white solid, which was used in the next step without purification.
Step 3- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) prop-2-yn-1-yl 4-methylbenzenesulfonate
A mixture of 3- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) prop-2-yn-1-ol (200 mg, crude), triethylamine (127 mg,1.26 mmol) and 4-methyl-benzenesulfonyl chloride (120 mg,0.63 mmol) in dichloromethane (10 ml) was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (20 ml) and extracted with dichloromethane (30 ml). The organic layer was washed with brine (20 ml), dried over sodium sulfate and evaporated under reduced pressure to give a crude residue which was purified by flash column chromatography on silica gel (eluting with 5% methanol in dichloromethane) to give 3- (5) - ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yn-1-yl 4-methylbenzenesulfonate as a white solid (130 mg, 49% yield).
Step 42- (2, 6-Dioxopiperidin-3-yl) -5- ((3- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) prop-2-yn-1-yl) oxy) isoindoline-1, 3-dione
To a solution of 3- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) prop-2-yn-1-yl 4-methylbenzenesulfonate (130 mg,0.21 mmol), potassium carbonate (85 mg,0.62 mmol) and 2- (2, 6-dioxopiperidin-3-yl) -5-hydroxyisoindoline-1, 3-dione (57 mg,0.21 mmol) in N, N-dimethylformamide (10 ml) under nitrogen was added potassium iodide (35 mg,0.21 mmol). The resulting mixture was warmed to 50 ℃ and stirred for 16 hours. TLC showed the reaction was complete. The reaction mixture was partitioned between water (20 ml) and ethyl acetate (20 ml). The organic layer was collected, washed with brine (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product which was purified by flash column chromatography on silica gel (eluting with 8% methanol in dichloromethane) to give 2- (2, 6-dioxopiperidin-3-yl) -5- ((3- (5- ((1 r,3 r) -3) - ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin-2-yl) oxy) prop-2-yn-1-yloxy) isoindoline-1, 3-dione (21.3 mg, 14%) as a yellow solid.
1H NMR(400MHz,CD3OD):δ1.92-1.94(m,1H),2.02-2.10(m,2H),2.62-2.65(m,5H),3.90(s,3H),4.97-5.02(m,2H),5.10(s,2H),5.37(t,J＝6Hz,1H),6.85(d,J＝8.4Hz,1H),7.20-7.22(m,1H),7.34-7.41(m,2H),7.45(d,J＝2.0Hz,1H),7.50-7.56(m,2H),7.75-7.77(m,2H),8.02-8.06(m,2H),8.21(d,J＝8.0Hz,1H),8.37(d,J＝6.0Hz,1H),8.42(d,J＝2.4Hz,1H),9.18(s,1H).(M+H)+ 733.4.
Compound 95, compound 97 (method of compound 94), compound 98, compound 183 (method of compound 73), compound 204 (combination of methods of compound 73 and compound 176) were prepared using a procedure similar to that described above for compound 83 (method of compound 94).
Synthetic schemes of exemplary Compound 102 and exemplary Compound 110
2- (2, 6-Dioxopiperidin-3-yl) -5- ((6- (6- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-3-yl) hex-5-yn-1-yl) oxy) isoindoline-1, 3-dione (exemplary compound 102) and 2- (2, 6-Dioxopiperidin-3-yl) -5- ((6- (6- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) pyridin-3-yl) hexyl) oxy) isoindoline-1, 3-dione (exemplary compound 110)
Step 1 7- (6- ((1 r,3 r) -3- ((5-iodopyridin-2-yl) oxy) cyclobutoxy) pyridin-3-yl) -5-methyl-5H-pyrido [4,3-b ] indole
To a solution of (1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutanol (100 mg,0.29 mmol) [ prepared by using a procedure similar to that described for steps 1 and 2 of compound 73 ] 1-methylpyrrolidin-2-one (5 ml) was added sodium hydride (60% in mineral oil) (58 mg,1.45 mmol), and the reaction mixture was stirred for 1 hour. 2-fluoro-5-iodopyridine (65 mg,0.29 mmol) was then added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. TLC showed the reaction was complete. The reaction was quenched with water (10 ml) at 0 ℃ and extracted with ethyl acetate (20 ml x 2). The combined organic layers were washed with water (20 ml x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluting with 5% methanol in dichloromethane) to give 7- (6- ((1 r,3 r) -3- ((5-iodopyridin-2-yl) oxy) cyclobutoxy) pyridin-3-yl) -5-methyl-5H-pyrido [4,3-b ] indole (100 mg, 63%) as a white solid.
7- (6- ((1 R,3 r) -3- ((5-iodopyridin-2-yl) oxy) cyclobutoxy) pyridin-3-yl) -5-methyl-5H-pyrido [4,3-b ] indole was converted to the title compound, 2- (2, 6-dioxopiperidin-3-yl) -5- ((6- (6- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin-2-yl) oxy) cyclohex-5-yn-1-yl) oxy) isoindoline-1, 3-dione (compound 102), and 2- (2, 6-dioxopiperidin-3-yl) -5- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) pyridin-3-yl) isoindoline (compound 110) using the procedure described for compound 73 below.
Compounds of formula (I) 102：1HNMR(400MHz,DMSO-d6):δ1.73(d,J＝7.2Hz,2H),1.91(d,J＝7.2Hz,2H),2.01-2.08(m,1H),2.51-2.67(m,8H),2.83-2.94(m,1H),3.96(s,3H),4.24(t,J＝6.0Hz,2H),5.12(dd,J＝12.8,5.2Hz,1H),5.31-5.52(m,2H),6.99(d,J＝8.4Hz,1H),6.83(d,J＝8.6Hz,1H),7.36(d,J＝8.2Hz,1H),7.44(s,1H),7.75-7.58(m,3H),7.82(d,J＝8.2Hz,1H),7.99(s,1H),8.10-8.28(m,2H),8.33(d,J＝8.2Hz,1H),8.52(s,1H),8.64(d,J＝1.6Hz,1H),9.40(s,1H),11.11(s,1H).(M+H)+ 775.5
Compounds of formula (I) 110：1H NMR(400MHz,DMSO-d6):δ1.36(d,J＝7.6Hz,2H),1.45(d,J＝6.8Hz,2H),1.52-1.61(m,2H),1.70-1.80(m,2H),1.98-2.02(m,3H),2.54-2.70(m,6H),2.89(t,J＝16.6Hz,1H),3.96(s,3H),4.16(d,J＝5.0Hz,2H),5.12(dd,J＝12.8,4.4Hz,1H),5.36-5.43(m,2H),6.77(d,J＝8.4Hz,1H),6.99(d,J＝8.0Hz,1H),7.34(d,J＝8.8Hz,1H),7.42(s,1H),7.60-7.64(m,3H),7.83(d,J＝8.0Hz,1H),7.97(dd,J＝14.0,6.4Hz,2H),8.33(d,J＝8.4Hz,1H),8.21(d,J＝8.0Hz,1H),8.50(d,J＝4.8Hz,1H),8.65(s,1H),9.37(s,1H),11.11(s,1H).(M+H)+ 779.5
Synthetic scheme for exemplary Compound 173
5- (2- ((3- (5- ((1 R,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) prop-2-yn-1-yl) oxy) ethoxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
Step 12- (prop-2-yn-1-yloxy) ethan-1-ol
To a stirred mixture of sodium hydride (60% in mineral oil, 115mg,2.8 mmol) in anhydrous N, N-dimethylformamide (20 ml) was added ethane-1, 2-diol (3.9 g,63 mmol) at 0℃and stirred at 0℃for 0.5 h. To the resulting mixture was added 3-bromoprop-1-yne (5.0 g,42 mmol) at 0℃and stirred overnight at 50 ℃. TLC showed the reaction was complete. The reaction mixture was quenched with ice water (20 ml) and partitioned between ethyl acetate (80 ml) and water (100 ml). The organic layer was collected and the aqueous layer was extracted with ethyl acetate (50 ml x 2). The combined organic layers were washed with brine (80 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluting with 0-20% ethyl acetate in hexane) to give 2- (prop-2-yn-1-yloxy) ethanol (3.4 g, yield 80%) as a colourless oil.
Step 2- (prop-2-yn-1-yloxy) ethyl 4-methylbenzenesulfonate
To a stirred solution of 2- (prop-2-yn-1-yloxy) ethanol (1 g,10 mmol), triethylamine (3 g,3 mmol) and N, N-dimethylpyridine-4-amine (20 mg,1 mmol) in dichloromethane (20 ml) at 0℃was added p-toluenesulfonic acid 2.9g,15 mmol. The reaction mixture was allowed to warm to room temperature and stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane (20 ml), washed with brine (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue. It was purified by flash column chromatography on silica gel (eluent 10-20% ethyl acetate in hexane) to give 2- (prop-2-yn-1-yloxy) ethyl 4-methylbenzenesulfonate as a pale yellow oil (700 mg, yield: 40%).
Step 3 2- (2, 6-Dioxopiperidin-3-yl) -5- (2- (prop-2-yn-1-yloxy) ethoxy) isoindoline-1, 3-dione
To a stirred solution of 2- (prop-2-yn-1-yloxy) ethyl 4-methylbenzenesulfonate (700 mg,2.8 mmol) and potassium carbonate (1.1 g,8.3 mmol) in N, N-dimethylformamide (15 ml) was added 2- (2, 6-dioxopiperidin-3-yl) -5-hydroxyisoindoline-1, 3-dione (755mg, 2.8 mmol) at room temperature. The resulting mixture was stirred at 50 ℃ overnight. TLC showed the reaction was complete. The mixture solution was cooled to room temperature. The reaction mixture was partitioned between ethyl acetate (20 ml) and water (30 ml), the organic layer was collected, and the aqueous layer was extracted with ethyl acetate (20 ml x 2). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluting with 0-50% ethyl acetate in hexane) to give 2- (2, 6-dioxopiperidin-3-yl) -5- (2- (prop-2-yn-1-yloxy) ethoxy) isoindoline-1, 3-dione (290 mg, 30% yield) as a pale yellow solid.
Using the procedure described for compound 73, 2- (2, 6-dioxopiperidin-3-yl) -5- (2- (prop-2-yn-1-yloxy) ethoxy) isoindoline-1, 3-dione was reacted with 7- (6- ((1 r,3 r) -3- ((6-iodopyridin-3-yl) oxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole to give the title compound, 5- (2- ((3- (5- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yn-1-yl) oxy) ethoxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione.
1H NMR(400MHz,DMSO-d6):δ2.02-2.08(m,1H),2.52-2.76(m,6H),2.85-2.93(m,1H),3.89-3.95(m,2H),4.37-4.42(m,2H),4.49(s,2H),5.06-5.14(m,2H),5.40-5.47(m,1H),6.99(d,J＝8.4Hz,1H),7.30-7.33(m,1H),7.38-7.40(m,1H),7.46-7.48(m,2H),7.62-7.64(m,2H),7.82-7.84(m,2H),8.14-8.17(m,1H),8.24(d,J＝2.8Hz,1H),8.36-8.38(m,1H),8.49(d,J＝6Hz,1H),8.58(d,J＝2.0Hz,1H),9.47(s,1H),11.11(s,1H),12.14-12.28(m,1H).(M+H)+ 763.5.
Compound 110 (method of compound 102), 124, 144 (method of compound 102), 145, 146, 147 (method of compound 94), 172 (method of compound 73), 179 (method of compound 173), 188 (method of compound 173), 189 (method of compound 73) were prepared using a similar procedure as described above.
Synthetic schemes for exemplary Compound 180
Step 1 tert-butyl (S) -5-amino-5-oxo-4- (1-oxo-5- (prop-2-yn-1-yloxy) isoindolin-2-yl) pentanoate
To a stirred solution of (S) -tert-butyl 5-amino-4- (5-hydroxy-1-oxoisoindolin-2-yl) -5-oxopentanoate (450 mg,1.35 mmol) and 3-bromoprop-1-yne (192 mg,1.62 mmol) in N, N-dimethylformamide (4 ml) was added potassium carbonate (372 mg,2.69 mmol) and potassium iodide (22.4 mg,0.135 mmol), and the mixture was stirred overnight at 50℃under nitrogen. LCMS showed formation of the desired product. The mixture was partitioned between ethyl acetate (50 ml) and water (30 ml). The organic layer was washed with brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue, which was purified by silica gel flash chromatography (eluting with 50% ethyl acetate in hexane, and 5% methanol was added) to give (S) -tert-butyl 5-amino-5-oxo-4- (1-oxo-5- (prop-2-yn-1-yloxy) isoindolin-2-yl) pentanoate (489 mg, yield 97%) as a colorless oil.
Step 2 3- (1-oxo-5- (prop-2-yn-1-yloxy) isoindolin-2-yl) piperidine-2, 6-dione
To a stirred solution of (S) -tert-butyl 5-amino-5-oxo-4- (1-oxo-5- (prop-2-yn-1-yloxy) isoindolin-2-yl) pentanoate (325 mg,0.873 mmol) in dry tetrahydrofuran (20 ml) under nitrogen atmosphere at 0℃was added dropwise potassium tert-butoxide (1N in THF) (107.7 mg,0.96 mmol). The reaction mixture was stirred at the same temperature for 20 minutes. LCMS showed formation of the desired product. The reaction mixture was quenched with water (20 ml) and extracted with ethyl acetate (50 ml). The organic layer was collected, washed with water (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue, which was purified by silica gel flash chromatography (eluting with 50% ethyl acetate in hexane, and 10% methanol was added) to give 3- (1-oxo-5- (prop-2-yn-1-yloxy) isoindolin-2-yl) piperidine-2, 6-dione (128 mg, yield 49%) as a white solid.
Step 3- (5- ((3- (5- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin-2-yl) cyclobutoxy) pyridin-2-yl) prop-2-yn-1-yl) oxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione
To a stirred solution of 3- (1-oxo-5- (prop-2-yn-1-yloxy) isoindolin-2-yl) piperidine-2, 6-dione (50 mg,0.168 mmol), 7- (6- ((1 r,3 r) -3- ((6-iodopyridin-3-yl) oxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole (74 mg,0.14 mmol) and triethylamine (70.7 mg,0.70 mmol) in N, N-dimethylformamide (1 ml) at room temperature under nitrogen atmosphere was added trans-dichlorobis (triphenylphosphine) palladium (II) (4.91 mg, 0.0071 mmol) and copper iodide (1.33 mg, 0.0070 mmol), and the mixture was degassed three times with nitrogen. The resulting mixture was stirred at 65 ℃ for 12 hours. TLC showed the reaction was complete. TLC showed the reaction was complete. The mixture was partitioned between ethyl acetate (50 ml) and water (30 ml). The organic layer was washed with brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by preparative TLC eluting with 10% methanol in dichloroethane to give 3- (5- ((3- (5- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin-2-yl) cyclobutoxy) pyridin-2-yn-1-yl) oxy) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (19 mg, 16%) as a white solid.
1HNMR(400MHz,DMSO-d6):δ1.97-2.00(m,1H),2.33-2.44(m,2H),2.55-2.67(m,4H),2.86-2.96(m,1H),4.29(d,J＝17.2Hz,1H),4.42(d,J＝16.8Hz,1H),5.06-5.10(m,2H),5.18(s,2H),5.42-5.45(m,1H),6.99(d,J＝8.4Hz,1H),7.17(d,J＝8.0Hz,1H),7.29-7.33(m,2H),7.50(d,J＝8.4Hz,1H),7.68(d,J＝8.0Hz,2H),7.74(d,J＝5.6Hz,1H),7.89(s,1H),8.16(d,J＝7.6Hz,1H),8.24(s,1H),8.41(d,J＝7.6Hz,1H),8.53-8.59(m,2H),9.56(s,1H),10.97(s,1H),12.54(br,1H).(M+H)+ 705.4.
Synthetic scheme for exemplary Compound 64
5- (4- (3- (5- ((1 R,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) propyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
The title compound was prepared according to the following protocol using the procedure described above for the other targets and conventional procedures known to those skilled in the art. The starting tert-butyl 7- (6- ((1 r,3 r) -3- ((6- (3-hydroxy prop-1-yn-1-yl) pyridin-3-yl) oxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole-5-carboxylate was prepared according to the procedure described for compound 117.
5- (4- (3- (5- ((1 R,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) propyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
1H NMR(400MHz,CD3OD)δ9.42(s,1H),8.53(d,J＝2.3Hz,1H),8.50(d,J＝6.1Hz,1H),8.38(d,J＝8.1Hz,1H),8.13(d,J＝8.0Hz,2H),7.87(s,1H),7.71–7.78(m,2H),7.68(d,J＝8.3Hz,1H),7.42(s,1H),7.33(s,2H),7.29(d,J＝8.6Hz,1H),6.99(d,J＝8.6Hz,1H),5.51(s,2H),5.06–5.14(m,2H),3.55(s,4H),2.58–3.03(m,15H),2.04(m,3H).
Synthetic scheme for exemplary Compound 67
Step 1:14- ((5-bromo-3- (trifluoromethyl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecan-1-ol
To a solution of pentaethylene glycol (330 mg,1.38 mmol) in THF (5 mL) at 0deg.C was added NaH (30 mg,0.76 mmol). The solution was stirred at room temperature for 1 hour. Then 5-bromo-2-chloro-3- (trifluoromethyl) pyridine (180 mg,0.69 mmol) was added. The resulting solution was stirred at 80 ℃ for 2 hours. The reaction solution was quenched with water. The mixture was extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the desired compound (400 mg, crude) which was used in the next step without further purification.
Step 2:14- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -3,6,9,12 tetraoxatetradecan-1-ol
14- ((5-Bromo-3- (trifluoromethyl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecan-1-ol
(180 Mg,0.39 mmol), 5-methyl-7- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -5H-pyrido [4,3-b ] ] indole (120 mg,0.39 mmol) [ prepared as described in step 1 of compound 63 ], pd (amphos) Cl 2 (20 mg, 10%) and CsF (118 mg,0.78 mmol) in dioxane/H 2 O (10/1, 5 mL) were stirred at 80℃for 2 hours. The reaction mixture was quenched with water. The mixture was extracted with ethyl acetate (20 mL). The organic layer was dried over Na 2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the desired compound (85 mg,47% yield).
Step 3 2- (2, 6-Dioxopiperidin-3-yl) -5- ((14- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) isoindoline-1, 3-dione
To a solution of 14- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecan-1-ol (85 mg,0.15 mmol), 2- (2, 6-dioxopiperidin-3-yl) -5-hydroxyisoindoline-1, 3-dione (41 mg,0.15 mmol) and PPh 3 (47 mg,0.18 mmol) in THF was added DIAD (45 mg,0.22 mmol) at 40 ℃. The mixture was stirred at 40 ℃ for 1 hour. The reaction solution was quenched with water. The mixture was extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (10 mL). The organic layer was dried over Na 2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (34 mg,28% yield).
1H NMR(400MHz,CD3OD):δ9.25(s,1H),8.79(s,1H),8.37–8.39(d,J＝8.0Hz,1H),8.28–8.30(d,J＝8.0Hz,2H),7.89(s,1H),7.63–7.65(d,J＝8.0Hz,1H),7.54–7.56(m,2H),7.26(s,1H),7.18–7.20(m,1H),5.02–5.05(m,1H),4.62–4.64(m,2H),4.17–4.19(m,2H),3.95(s,3H),3.88–3.90(m,2H),3.82–3.84(m,2H),3.61–3.71(m,13H),2.55–2.81(m,3H),2.95–2.99(m,1H).(M+H)+ 820.5.
Using the procedure of compound 67, the following was prepared, compound 69, compound 113.
Synthetic scheme for exemplary Compound 65
Step 1:4- ((1 r,3 r) -3- (benzyloxy) cyclobutoxy) pyridine
To a solution of pyridin-4-ol (3.20 g,33.66mmol,1.5 eq.) and 3-benzyloxycyclobutanol (4 g,22.44mmol,1 eq.) in tetrahydrofuran (200 mL) under nitrogen at 10℃was added one portion of triphenylphosphine (7.06 g,26.93mmol,1.2 eq.) and diisopropyl azodicarboxylate (5.45 g,26.93mmol,1.2 eq.). The mixture was stirred at 50 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran. Water (50 mL) was poured into the mixture and stirred for 1 min. The aqueous phase was extracted with dichloromethane (50 ml x 3). The combined organic phases were washed with brine (50 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (20:1 to 5:1 petroleum ether: tetrahydrofuran). HPLC showed 41% product at 254 mm. The residue was purified by flash C18 column chromatography [ acetonitrile: water (0.5% ammonium hydroxide) =5% -50% ]. The compound 4- (3-benzyloxybutyloxy) pyridine (3.2 g,12.53mmol,55% yield) was obtained as a white solid.
Step2 1-benzyl-4- ((1 r,3 r) -3- (benzyloxy) cyclobutoxy) pyridin-1-ium bromide
To a solution of 4- (3-benzyloxybutyloxy) pyridine (4.2 g,16.45mmol,1 eq.) in toluene (65 mL) was added benzyl bromide (2.81 g,16.45mmol,1 eq.). The mixture was stirred at 80 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to remove toluene. The crude product was triturated with petroleum ether (80 mL). The compound 1-benzyl-4- ((1 r,3 r) -3- (benzyloxy) cyclobutoxy) pyridin-1-ium bromide (6.5 g,15.25mmol,92% yield) was obtained as a white solid.
Step 3 1-benzyl-4- ((1 r,3 r) -3- (benzyloxy) cyclobutoxy) -1,2,3, 6-tetrahydropyridine
To a solution of 1-benzyl-4- ((1 r,3 r) -3- (benzyloxy) cyclobutoxy) pyridin-1-ium bromide (6.5 g,15.25mmol,1 eq.) in ethanol (120 mL) at 0 ℃ was added sodium borohydride (3.46 g,91.47mmol,6 eq.). The mixture was stirred at 15 ℃ for 4 hours. The reaction mixture was concentrated under reduced pressure to remove ethanol. The residue was diluted with water (25 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated brine (40 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The compound 1-benzyl-4- (3-benzyloxycyclobutoxy) -3, 6-dihydro-2H-pyridine (4.5 g,12.88mmol,84% yield) was obtained as a colorless oil.
Step 4 (1 r,3 r) -3- ((1-Benzylpiperidin-4-yl) oxy) cyclobutan-1-ol
To a solution of 1-benzyl-4- (3-benzyloxybutyloxy) -3, 6-dihydro-2H-pyridine (4.5 g,12.88mmol,1 eq.) in tetrahydrofuran (95 mL) and ethanol (70 mL) under nitrogen atmosphere was added palladium (0.5 g,10% purity) on an activated carbon catalyst. The suspension was degassed and purged 3 times with hydrogen. The mixture was stirred under hydrogen (50 Psi) at 25 ℃ for 24 hours. LCMS showed reaction incomplete. The mixture was then stirred at 35 ℃ for 12 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (20:1:0 to 10:1:0.1 dichloromethane: methanol: ammonium hydroxide). The compound 3- [ (1-benzyl-4-piperidinyl) oxy ] cyclobutanol (2.8 g,10.71mmol,83% yield) was obtained as a colorless oil.
Step5 tert-butyl 4- ((1 r,3 r) -3-hydroxycyclobutoxy) piperidine-1-carboxylate
To a solution of 3- [ (1-benzyl-4-piperidinyl) oxy ] cyclobutanol (1.1 g,4.21mmol,1 eq.) in methanol (10 mL) under nitrogen atmosphere were added palladium hydroxide (591 mg) and di-tert-butyl carbonate (1.84 g,8.42mmol,2 eq.). The suspension was degassed and purged 3 times with hydrogen. The mixture was stirred under hydrogen (50 Psi) at 25 ℃ for 12 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate=20:1 to 2:1). The compound tert-butyl 4- (3-hydroxycyclobutoxy) piperidine-1-carboxylate (630 mg,3.02mmol,71% yield) was obtained as a colorless oil.
Step 6 tert-butyl 4- ((1 r,3 r) -3- ((5-bromopyridin-2-yl) oxy) cyclobutoxy) piperidine-1-carboxylate
To a mixture of tert-butyl 4- (3-hydroxycyclobutoxy) piperidine-1-carboxylate (400 mg,1.47mmol,1 eq.) and 5-bromo-2-fluoro-pyridine (284 mg,1.62mmol,1.1 eq.) in dimethylformamide (8 mL) at 25 ℃ was added one portion of cesium carbonate (960 mg,2.95mmol,2 eq.) under nitrogen atmosphere. The mixture was stirred at 100 ℃ for 2 hours. The reaction mixture was poured into water (30 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (20 ml x 3). The combined organic phases were washed with brine (30 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (1000 mesh silica gel, 200:1 to 20:1 petroleum ether/ethyl acetate). The product, tert-butyl 4- [3- [ (5-bromo-2-pyridinyl) oxy ] cyclobutoxy ] piperidine-1-carboxylic acid ester (560 mg,1.30mmol,88% yield), was obtained as a colorless oil.
Step 7 tert-butyl 4- ((1 r,3 r) -3- ((5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridin-2-yl) oxy) cyclobutoxy) piperidine-1-carboxylate
To tert-butyl 4- [3- [ (5-bromo-2-pyridinyl) oxy ] cyclobutoxy ] piperidine-1-carboxylate (560 mg,1.31mmol,1 eq.) 4,4', 5', to a suspension of 5' -octamethyl-2, 2' -bis (1, 3, 2-dioxaborane) (432 mg,1.70mmol,1.3 eq.) and potassium acetate (257 mg,2.62mmol,2 eq.) in dioxane (20 mL) was added [1,1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride (95 mg,0.13mmol,0.1 eq.). The mixture was degassed in vacuo and purged 3 times with nitrogen. The mixture was heated to 80 ℃ and stirred at 80 ℃ for 15 hours. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (20:1 to 10:1 petroleum ether/ethyl acetate). Tert-butyl 4- [3- [ [5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2-pyridinyl ] oxy ] cyclobutoxy ] piperidine-1-carboxylate (500 mg,1.05mmol,80% yield) was obtained as a colorless oil.
Step 8 tert-butyl 4- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) piperidine-1-carboxylic acid ester
To a solution of tert-butyl 4- [3- [ [5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2-pyridinyl ] oxy ] cyclobutoxy ] piperidine-1-carboxylate (240 mg,0.50mmol,1 eq.), 7-bromo-5H-pyrido [4,3-b ] indole (125 mg,0.50mmol,1 eq.) and potassium carbonate (140 mg,1.01mmol,2 eq.) in a mixture of dimethylformamide (8 mL) and water (2 mL) was added [1,1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride (37 mg,0.05mmol,0.1 eq.). The mixture was degassed in vacuo and purged three times with nitrogen. The mixture was stirred at 100 ℃ for 3 hours. The mixture was poured into 50mL of saturated brine, and then extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (50 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (dichloromethane: methanol=20:1). Tert-butyl 4- [3- [ [5- (5H-pyrido [4,3-b ] indol-7-yl) -2-pyridinyl ] oxy ] cyclobutoxy ] piperidine-1-carboxylic acid ester (175 mg,0.34mmol,67% yield) was obtained as an off-white solid.
Step 9 7- (6- ((1 r,3 r) -3- (piperidin-4-yloxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole
A solution of tert-butyl 4- [3- [ [5- (5H-pyrido [4,3-b ] indol-7-yl) -2-pyridinyl ] oxy ] cyclobutoxy ] piperidine-1-carboxylic acid ester (170 mg,0.33mmol,1 eq.) in hydrochloric acid (4M in dioxane, 8mL,100 eq.) was stirred at 25℃for 10 min. The mixture was concentrated in vacuo. The product 7- [6- [3- (4-piperidinyloxy) cyclobutoxy ] -3-pyridinyl ] -5H-pyrido [4,3-b ] indole (190 mg, crude, hydrochloride) was obtained as a brown solid and used in the next step without further purification.
Step 10 5- ((5, 5-Dimethoxypentyl) oxy) -2- (2, 6-Dioxopiperidin-3-yl) isoindoline-1, 3-dione
To a solution of 2- (2, 6-dioxopiperidin-3-yl) -5-hydroxyisoindoline-1, 3-dione (268 mg,2.00mmol,1 eq.) and 5-bromo-1, 1-dimethoxypentane (506 mg,2.40mmol,1.2 eq.) in a mixture of acetone (3 mL) and dimethylformamide (3 mL) was added potassium carbonate (552 mg,4.00mmol,2 eq.). The mixture was heated to 50 ℃ and stirred at 50 ℃ for 2 hours. The mixture was poured into 50ml of 0.1m aqueous hydrochloric acid and then extracted with ethyl acetate (50 ml x 2). The combined organic layers were washed with brine (50 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (dichloromethane: methanol=20:1). 5- ((5, 5-Dimethoxypentyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (120 mg,0.30mmol,14% yield) was obtained as a colourless oil.
Step 11- ((2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) valeraldehyde
To a mixture of 5- (5, 5-dimethoxypentoxy) -2- (2, 6-dioxo-3-piperidinyl) isoindoline-1, 3-dione (120 mg,0.29mmol,1 eq.) in tetrahydrofuran (10 mL) at 25 ℃ was added a portion of sulfuric acid (2 m in water, 7mL,50 eq.) under nitrogen atmosphere. The mixture was stirred at 70 ℃ for 1 hour. The aqueous phase was extracted with ethyl acetate (20 ml x 3). The combined organic phases were washed with saturated aqueous sodium bicarbonate (20 ml x 2) then brine (20 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product 5- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxo-isoindolin-5-yl ] oxovaleraldehyde (93 mg, crude) was obtained as a pale yellow solid.
Step 12 5- ((5- (4- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) piperidin-1-yl) pentyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
To a mixture of 7- [6- [3- (4-piperidinyloxy) cyclobutoxy ] -3-pyridinyl ] -5H-pyrido [4,3-b ] indole (110 mg,0.24mmol,1 eq. Hydrochloride) in dichloroethane (2 mL) and methanol (5 mL) at 20℃was added a portion of sodium acetate (40 mg,0.49mmol,2 eq.). The mixture was stirred at 20 ℃ for 10 minutes. 5- [2- (2, 6-dioxo-3-piperidyl) -1, 3-dioxo-isoindolin-5-yl ] oxovaleraldehyde (88 mg,0.24mmol,1 eq.) was added. The mixture was stirred at 20 ℃ for 10 minutes. Then acetic acid (0.02 mL) and sodium cyanoborohydride (31 mg,0.49mmol,2 eq.) were added. The mixture was stirred at 35 ℃ for 40 minutes. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by semi-preparative reverse phase HPLC (column: phenomenex Synergi C18:150:25:10 um; mobile phase: [ water (0.225% formic acid) -acetonitrile ]; B%:3% -33%,10 min). The product 2- (2, 6-dioxo-3-piperidyl) -5- [5- [4- [3- [ [5- (5H-pyrido [4,3-b ] indol-7-yl) -2-pyridyl ] oxy ] cyclobutoxy ] -1-piperidyl ] pentoxy ] isoindoline-1, 3-dione tricarboxylic acid ester (50.2 mg,0.05mmol,21% yield) was obtained as an off-white solid.
1H NMR:(400MHz,DMSO-d6)δ:11.80(s,1H),11.11(s,1H),9.35(s,1H),8.55(d,J＝2.4Hz,1H),8.42(d,J＝5.6Hz,1H),8.29(d,J＝8.4Hz,1H),8.18(s,3H),8.11(dd,J＝2.4,8.8Hz,1H),7.83(d,J＝8.4Hz,1H),7.76(s,1H),7.55(d,J＝8.4Hz,1H),7.48(d,J＝5.6Hz,1H),7.42(d,J＝2.0Hz,1H),7.35(dd,J＝2.0,8.4Hz,1H),6.92(d,J＝8.4Hz,1H),5.30(d,J＝3.6Hz,1H),5.11(dd,J＝5.6,13.2Hz,1H),4.35(t,J＝6.4Hz,1H),4.17(t,J＝6.4Hz,2H),2.93–2.84(m,2H),2.77(s,2H),2.63–2.54(m,3H),2.37(d,J＝6.0Hz,4H),2.22–1.98(m,4H),1.87–1.74(m,4H),1.53–1.38(m,6H).(M+H)+ 757.5
Compounds 82, 123 (as described for compounds 65 and 67 and as detailed in the schemes below) were prepared using procedures similar to those described above.
Synthetic scheme for exemplary Compound 66
5- (4- (2- (4- ((1 R,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) piperidin-1-yl) ethyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
Step 1 benzyl 4- (2, 2-diethoxyethyl) piperazine-1-carboxylate
To a solution of benzylpiperazine-1-carboxylate (1.0, 4.54 mmol) in DMF (20 mL) was added K 2CO3 (1.25 g,9.0 mmol) and 2-bromo-1, 1-diethoxyethane (1.0 g,4.54 mmol). The resulting mixture was stirred at 80 ℃ for 20 hours. The reaction mixture was then diluted with water (50 mL) and extracted with EA. The organic phase was washed with brine, dried over MgSO 4 and concentrated. The residue was purified by chromatography (silica gel, PE: ea=1:1) to give the desired compound benzyl 4- (2, 2-diethoxyethyl) piperazine-1-carboxylate (1.55 g) as a colourless oil.
Step 2 1- (2, 2-diethoxyethyl) piperazine
To a solution of benzyl 4- (2, 2-diethoxyethyl) piperazine-1-carboxylate (1.55 g,4.6 mmol) in MeOH (30 mL) was added Pd (OH) 2/C (0.3 g, 20%). The resulting mixture was stirred at 30 ℃ for 3 hours. The reaction mixture was then filtered and concentrated to give the desired compound 1- (2, 2-diethoxyethyl) piperazine (0.9 g, crude) as a white solid, which was used in the next step without further purification.
Step 35- (4- (2, 2-Diethoxyethyl) piperazin-1-yl) -2- (2, 6-Dioxopiperidin-3-yl) isoindoline-1, 3-dione
To a solution of 1- (2, 2-diethoxyethyl) piperazine (0.9 g,4.45 mmol) in NMP (15 mL) was added DIEA (2.3 g,17.8 mmol) and 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (1.35 g,4.9 mmol). The resulting mixture was stirred at 90 ℃ for 20 hours. The reaction mixture was then diluted with water (50 mL) and extracted with DCM/MeOH (10/1). The organic phase was washed with brine, dried over MgSO 4 and concentrated. The residue was purified by chromatography (silica gel, DCM: meOH (20:1) to give the desired compound (1.4 g) as a yellow solid.
Step 4 2- (4- (2, 6-Dioxopiperidin-3-yl) -1, 3-Dioxoisoindolin-5-yl) piperazin-1-yl) acetaldehyde
A solution of 5- (4- (2, 2-diethoxyethyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (300 mg,0.65 mmol) in HCl (5 mL,2.5mol/L in H 2 O) was stirred at 50℃for 20 hours. The mixture was basified with NaHCO 3 (20 mL) and extracted with EA. The organic phase was washed with brine, dried over MgSO 4 and concentrated to give the desired compound (220 mg, crude) as a yellow solid, which was used in the next step without further purification.
Step 5- (4- (2- (4- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) piperidin-1-yl) ethyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
To a solution of 2- (4- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperazin-1-yl) acetaldehyde (180 mg,0.41 mmol) in MeOH/DMSO (8 mL, 1/1) was added 7- (6- ((1 r,3 r) -3- (piperidin-4-yloxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole (97 mg,0.24 mmol) [ prepared as described in Compound 65 ], acOH (1 drop) and NaBH 3 CN (60 mg,0.94 mmol). The resulting mixture was stirred at 10 ℃ for 2 hours. The reaction mixture was then diluted with water (10 mL) and extracted with EA. The organic phase was washed with brine and filtered, and the crude material was purified by preparative HPLC to give the title compound (21.2 mg) as a yellow solid.
1H NMR(400MHz,DMSO-d6):δ13.21(s,1H),11.08(s,2H),9.76(s,1H),8.67(d,J＝6.6Hz,1H),8.61(s,1H),8.52(d,J＝8.3Hz,1H),8.17(d,J＝8.3Hz,1H),8.02(d,J＝7.1Hz,2H),7.82–7.72(m,3H),7.46(s,2H),7.35(s,2H),6.96(d,J＝8.5Hz,1H),5.34(s,1H),5.08(d,J＝7.7Hz,2H),4.40(s,2H),3.23(s,4H),3.15(s,4H),3.02(s,4H),2.95–2.83(m,4H),2.59(d,J＝15.7Hz,4H),2.44(s,2H),2.01(s,5H),1.77(d,J＝14.7Hz,2H).(M+H)+ 783.6.
Synthetic scheme for exemplary Compound 171
5- ((4, 4-Difluoro-5- (4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) piperidin-1-yl) pentyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
Step 1O 5-tert-butyl O1-ethyl 2, 2-difluoroglutarate
A mixture of tert-butylprop-2-enoate (10 g,78.02mmol,1.00 eq), ethyl 2-bromo-2, 2-difluoroacetate (28.51 g,140.44mmol,1.8 eq) and copper (10.41 g,163.85mmol,2.10 eq) in tetrahydrofuran (100 mL) was heated to 55℃with vigorous stirring, then N, N, N ', N' -tetramethyl ethylenediamine (4.53 g,39.01mmol,0.50 eq) was added followed by acetic acid (4.22 g,70.22mmol,0.90 eq). The dark blue-brown reaction mixture was stirred at 55 ℃ for 1 hour. 10% aqueous ammonium chloride (100 mL) and ethyl acetate (500 mL) were added. The resulting mixture was stirred at room temperature for 0.5 hours and filtered through celite. The organic phase was washed with another portion of ammonium chloride solution (100 ml×5) to remove the remaining copper complex (blue). The solution was dried over anhydrous sodium sulfate, filtered and evaporated under vacuum. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=500/1, 100/1) to give O5-tert-butyl O1-ethyl 2, 2-difluoroglutarate as a yellow oil (18.6 g,73.74mmol,95% yield).
Step 2 t-butyl 4, 4-difluoro-5-hydroxy-pentanoate
A suspension of sodium borohydride (3.24 g,85.63mmol,1.20 eq.) in ethanol (100 mL) was cooled to 0deg.C in an ice bath and a solution of O5-tert-butyl O1-ethyl 2, 2-difluoroglutarate (18 g,71.36mmol,1.00 eq.) in ethanol (100 mL) was added dropwise from an addition funnel with vigorous stirring. The rate of addition was carefully controlled to maintain the reaction mixture temperature at 0-15 ℃. The mixture was then stirred at 15 ℃ for 1 hour. The reaction mixture was quenched by dropwise addition of 5% aqueous citric acid (40 mL) with cooling. The aqueous phase was extracted with ethyl acetate (200 mL. Times.3). The combined organic phases were washed with brine (200 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=20/1, 10/1) to give tert-butyl 4, 4-difluoro-5-hydroxy-pentanoate (14.2 g,67.55mmol,95% yield) as a colourless oil.
Step 3 t-butyl 4, 4-difluoro-5-tetrahydropyran-2-yl oxopentanoate
To a mixture of tert-butyl 4, 4-difluoro-5-hydroxy-pentanoate (14.2 g,67.55mmol,1.00 eq.) and 4-methylbenzenesulfonic acid (640 mg,3.38mmol,0.05 eq.) in dichloromethane (50 mL) at-10 ℃ was added 3, 4-dihydro-2H-pyran (17.05 g,202.65mmol,3.00 eq.) under nitrogen. The mixture was then warmed to 25 ℃ and stirred for 16 hours. The reaction was quenched with saturated sodium bicarbonate solution (50 mL) and then extracted with dichloromethane (50 mL x 3). The combined organic phases were washed with brine (50 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=500/1, 100/1) to give tert-butyl 4, 4-difluoro-5-tetrahydropyran-2-yl oxopentanoate (17.2 g, crude) as a colorless oil.
Step 4, 4-difluoro-5-tetrahydropyran-2-yloxy-pent-1-ol
To a solution of lithium aluminum hydride (2.66 g,70.12mmol,1.20 eq.) in tetrahydrofuran (300 mL) under nitrogen was added dropwise a solution of tert-butyl 4, 4-difluoro-5-tetrahydropyran-2-yloxy-pentanoate (17.2 g,58.44mmol,1.00 eq.) in tetrahydrofuran (60 mL) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 1 hour. The reaction was quenched by water (2.6 mL), aqueous sodium hydroxide (15%, 5.2 mL) and water (8 mL) at 0 ℃. The suspension was filtered through a pad of celite. The filter cake was washed with ethyl acetate (500 mL). The combined organic phases were washed with brine (200 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=20/1 to 10:1). 4, 4-difluoro-5-tetrahydropyran-2-yloxy-pent-1-ol (10.9 g,48.61mmol,83% yield) was obtained as a colorless oil.
Step 5 (4, 4-difluoro-5-tetrahydropyran-2-yloxy-pentyl) 4-methylbenzenesulfonate
To a mixture of 4, 4-difluoro-5-tetrahydropyran-2-yloxy-pentan-1-ol (10.9 g,48.61mmol,1.00 eq.) and p-toluenesulfonyl chloride (13.90 g,72.91mmol,1.50 eq.) in dichloromethane (100 mL) under nitrogen at 0 ℃ was added one portion of triethylamine (9.84 g,97.22mmol,2.00 eq.). The mixture was warmed to 25 ℃ and stirred for 16 hours. The mixture was poured into ice water (w/w=1/1) (30 mL) and stirred for 15 minutes. The aqueous phase was extracted with ethyl acetate (50 mL. Times.3). The combined organic phases were washed with brine (50 ml×2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=20/1, 10/1) to give (4, 4-difluoro-5-tetrahydropyran-2-yloxy-pentyl) 4-methylbenzenesulfonate (16.6 g,43.87mmol,90% yield) as a colorless oil.
Step 6 dimethyl 4- (4, 4-difluoro-5-hydroxy-pentoxy) benzene-1, 2-dicarboxylic acid ester
To a solution of (4, 4-difluoro-5-tetrahydropyran-2-yloxy-pentyl) 4-methylbenzenesulfonate (1 g,2.64mmol,1 eq.) in N, N-dimethylformamide (6 mL) was added cesium carbonate (1.72 g,5.28mmol,2 eq.) and dimethyl 4-hydroxybenzene-1, 2-dicarboxylic acid ester (553mg, 2.64mmol,1 eq.). The mixture was stirred at 50 ℃ for 12 hours. LCMS showed starting material consumed and desired compound was found. The mixture was filtered and poured into hydrochloric acid (1 n,30 ml) and the aqueous phase extracted with dichloromethane (20 ml x 3). The combined organic phases were washed with brine (20 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=20/1, 5/1). Dimethyl 4- (4, 4-difluoro-5-hydroxy-pentoxy) benzene-1, 2-dicarboxylic acid ester (700 mg,2.11mmol,79% yield) was obtained as a colorless oil.
Step 7 dimethyl 4- [4, 4-difluoro-5- (trifluoromethylsulfonyloxy) pentoxy ] benzene-1, 2-dicarboxylic acid ester
To a solution of dimethyl 4- (4, 4-difluoro-5-hydroxy-pentoxy) benzene-1, 2-dicarboxylic acid ester (600 mg,1.81mmol,1 eq.) in methylene chloride (10 mL) at 0 ℃ was added dropwise 2, 6-lutidine (580 mg,5.42mmol,3 eq.). After the addition, the mixture was stirred at this temperature for 10 minutes, then trifluoromethanesulfonyl triflate (2.55 g,9.03mmol,5 eq.) was added dropwise at 0 ℃. The resulting mixture was stirred at 25 ℃ for 50 minutes. LCMS showed the disappearance of starting material and the discovery of the desired compound. The mixture was concentrated in vacuo. The residue was further purified by preparative thin layer chromatography (petroleum ether: ethyl acetate=4:1). Dimethyl 4- [4, 4-difluoro-5- (trifluoromethylsulfonyloxy) pentoxy ] benzene-1, 2-dicarboxylic acid ester (600 mg,1.29mmol,71% yield) was obtained as a white solid.
Step 8 dimethyl 4- [4, 4-difluoro-5- [4- [3- [ [5- (5-methylpyrido [4,3-b ] indol-7-yl) -2-pyridinyl ] oxy ] cyclobutoxy ] -1-piperidinyl ] pentoxy ] benzene-1, 2-dicarboxylic acid ester
To a solution of dimethyl 4- [4, 4-difluoro-5- (trifluoromethylsulfonyloxy) pentoxy ] benzene-1, 2-dicarboxylic acid ester (150 mg,0.3mmol,1 eq.) in acetonitrile (1 mL) and dimethyl sulfoxide (0.5 mL) was added potassium carbonate (133 mg,1mmol,3 eq.) and 5-methyl-7- [6- [3- (4-piperidinyloxy) cyclobutoxy ] -3-pyridinyl ] pyrido [4,3-b ] indole (138 mg,0.3mmol,1 eq.) [ prepared as described for compound 82 ]. The mixture was stirred at 50 ℃ for 16 hours. LCMS showed almost disappearance of starting material and found the desired compound poured the mixture into water (20 mL) and the aqueous phase extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with brine (20 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was further purified by preparative thin layer chromatography (petroleum ether: ethyl acetate=4:1). Dimethyl 4- [4, 4-difluoro-5- [4- [3- [ [5- (5-methylpyrido [4,3-b ] indol-7-yl) -2-pyridinyl ] oxy ] cyclobutoxy ] -1-piperidinyl ] pentoxy ] benzene-1, 2-dicarboxylic acid ester (160 mg,0.2mmol,66% yield) was obtained as a yellow oil.
Step 9 4- [4, 4-difluoro-5- [4- [3- [ [5- (5-methylpyrido [4,3-b ] indol-7-yl) -2-pyridinyl ] oxy ] cyclobutoxy ] -1-piperidinyl ] pentoxy ] phthalic acid
To a solution of dimethyl 4- [4, 4-difluoro-5- [4- [3- [ [5- (5-methylpyrido [4,3-b ] indol-7-yl) -2-pyridinyl ] oxy ] cyclobutoxy ] -1-piperidinyl ] pentoxy ] benzene-1, 2-dicarboxylic acid ester (120 mg,0.16mmol,1 eq.) in methanol (3 mL) and water (1.5 mL) was added potassium hydroxide (36 mg,0.6mmol,4 eq.). The mixture was stirred at 55 ℃ for 2 hours. LCMS showed starting material consumed and desired compound was found. The reaction mixture was adjusted to ph= (7) by hydrochloric acid (1M) and concentrated under reduced pressure to remove methanol and water. The residue was used in the next step without further purification. 4- [4, 4-difluoro-5- [4- [3- [ [5- (5-methylpyrido [4,3-b ] indol-7-yl) -2-pyridinyl ] oxy ] cyclobutoxy ] -1-piperidinyl ] pentoxy ] phthalic acid (110 mg,0.1mmol,95% yield) was obtained as a yellow solid.
Step 10 5- [4, 4-difluoro-5- [4- [3- [ [5- (5-methylpyrido [4,3-b ] indol-7-yl) -2-pyridinyl ] oxy ] cyclobutoxy ] -1-piperidinyl ] pentoxy ] -2- (2, 6-dioxo-3-piperidinyl) isoindoline-1, 3-dione
To a solution of 4- [4, 4-difluoro-5- [4- [3- [ [5- (5-methylpyrido [4,3-b ] indol-7-yl) -2-pyridinyl ] oxy ] cyclobutoxy ] -1-piperidinyl ] pentoxy ] phthalic acid (110 mg,0.2mmol,1 eq.) in acetic acid (2 mL) was added sodium acetate (37 mg,0.5mmol,3 eq.) and the mixture stirred at 25 ℃ for 1 hour. 3-aminopiperidine-2, 6-dione (30 mg,0.2mmol,1.2 eq. Hydrochloric acid) was then added to the mixture and heated to 120℃and stirred for a further 11 hours. LCMS showed starting material consumed and desired compound was found. The mixture was concentrated in vacuo. Purifying the residue by preparative high performance liquid chromatography column (Phenomenex Synergi C18.150.25.10 um), mobile phase [ water (0.225% formic acid) -acetonitrile ]; B%:14% -35%, 7 min. 5- [4, 4-difluoro-5- [4- [3- [ [5- (5-methylpyrido [4,3-b ] indol-7-yl) -2-pyridinyl ] oxy ] cyclobutoxy ] -1-piperidinyl ] pentoxy ] -2- (2, 6-dioxo-3-piperidinyl) isoindoline-1, 3-dione (67 mg,0.08mmol,50% yield, 98% purity, formic acid) was obtained as a grey solid.
1H NMR:(400MHz,DMSO-d6)δ＝11.11(s,1H),δ＝9.35(s,1H)δ＝8.64(s,1H),8.49–8.48(d,J＝4Hz 1H),8.33-8.31(d,J＝8Hz 1H),δ＝8.17(s,1H),δ＝7.97(s,1H)7.85–7.83(d,J＝8Hz 1H),7.62–7.61(d,J＝4Hz 2H),7.43(s,1H),6.94–6.92(d,J＝8Hz 1H),5.31-5.29(m,1H),5.12–5.10(m,1H),4.34(s,5H),4.25-4.23(d,J＝8Hz 1H),3.95(s,3H),2.77(m,2H),2.73(m,4H),2.53-2.52(m,1H),2.39-2.38(m,4H),1.91-1.90(m,4H),1.75(m,2H),1.43(m,2H),1.41(m,2H).(M+H)+ 807.5.
Synthetic scheme for exemplary Compound 164
Step1 benzyl 6- (tosyloxy) hexanoate
To a mixture of benzyl 6-hydroxycaproate (1.1 g,4.95 mmol) and triethylamine (1.0 g,9.90 mmol) in dichloromethane (10 ml) at 0℃was added 4-toluenesulfonyl chloride (1.88 g,9.90 mmol). The mixture was stirred at room temperature for 1 hour. TLC showed the reaction was complete. The reaction mixture was diluted with dichloromethane (20 ml), washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluting with 30-50% ethyl acetate in hexane) to give benzyl 6- (tosyloxy) hexanoate (960 mg, 54% yield) as a colorless oil.
Step 2 benzyl 6- (2, 6-Dioxopiperidin-3-yl) -1, 3-Dioxoisoindolin-5-yloxy) hexanoate
A mixture of benzyl 6- (tosyloxy) hexanoate (200 mg,0.53 mmol) and 2- (2, 6-dioxopiperidin-3-yl) -5-hydroxyisoindoline-1, 3-dione (146 mg,0.53 mmol), potassium carbonate (147 mg,1.06 mmol) and potassium iodide (9 mg,0.05 mmol) in N, N-dimethylformamide (3 ml) was stirred at 50℃for 12 hours. TLC showed the reaction was complete. The reaction mixture was partitioned between water (15 ml) and ethyl acetate (15 ml). The organic layer was collected, washed with brine (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluting with 2-5% methanol in dichloromethane) to give benzyl 6- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yloxy) hexanoate (100 mg, 40% yield) as a yellow solid.
Step 3 6- (2, 6-Dioxopiperidin-3-yl) -1, 3-Dioxoisoindolin-5-yloxy) hexanoic acid
A mixture of benzyl-6- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yloxy) hexanoate (100 mg,0.21 mmol) and palladium on activated carbon (20%, 50 mg) in methanol (2 ml) was stirred at room temperature under hydrogen atmosphere (hydrogen balloon) for 1 hour. TLC showed the reaction was complete. The reaction mixture was filtered and concentrated under reduced pressure to give 6- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yloxy) hexanoic acid (70 mg, 86% yield) as a yellow oil which was used in the next step without further purification.
Step 4 5- (6- (4- ((1 r,3 r) -3- (5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yloxy) cyclobutoxy) piperidin-1-yl) -6-oxohexyloxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
To a mixture of 6- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yloxy) hexanoic acid (70 mg,0.18 mmol) and 7- (6- ((1 r,3 r) -3- (piperidin-4-yloxy) cyclobutoxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole (75 mg,0.18 mmol) [ prepared as described in compound 65 ] and triethylamine (56 mg,0.56 mmol) in N, N-dimethylformamide (2 ml) was added (2- (7-aza-1H-benzotriazol-1-yl) -1, 3-tetramethyluronium hexafluorophosphate) (212 mg,0.56 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour. TLC showed the reaction was complete. The reaction mixture was diluted with dichloromethane (50 ml), washed with brine (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluting with 2-5% methanol in dichloromethane) to give the title compound (6.6 mg, yield 5%) as a white solid.
1H NMR(400MHz,CDCl3):δ1.52-1.57(m,3H),1.61-1.65(m,2H),1.70-1.74(m,2H),1.98-2.01(m,2H),2.13-2.17(m,1H),2.34-2.41(m,2H),2.47-2.50(m,2H),2.78-2.88(m,2H),3.20-3.28(m,2H),3.54-3.72(m,3H),4.00-4.10(m,3H),4.39-4.44(m,1H),4.95(dd,J＝5.2,12.0Hz,1H),5.31-5.42(m,4H),6.82(d,J＝8.4Hz,1H),7.17(d,J＝8.8Hz,1H),7.31-7.34(m,2H),7.48-7.51(m,2H),7.68(s,1H),7.77(d,J＝8.8Hz,1H),7.87(d,J＝7.2Hz,1H),8.11(d,J＝8.0Hz,1H),8.32(s,1H),8.41-8.45(m,2H),9.23(s,1H).
Synthetic schemes for exemplary Compounds 198 and 205
2- (2, 6-Dioxopiperidin-3-yl) -5- ((3- (3- (4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) piperidin-1-yl) phenyl) prop-2-yn-1-yl) oxy) isoindoline-1, 3-dione
2- (2, 6-Dioxopiperidin-3-yl) -5- (3- (3- (4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) piperidin-1-yl) phenyl) propoxy) isoindoline-1, 3-dione
Using the above procedure and conventional procedures known to those skilled in the art, compounds 198 and 205 were prepared according to the following synthetic schemes:
Synthetic scheme for exemplary Compound 68
2- (2, 6-Dioxopiperidin-3-yl) -5- (4- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pentyl) piperazin-1-yl) isoindoline-1, 3-dione
Prepared according to the following synthetic schemes using the procedures described above and conventional procedures known to those skilled in the art.
1H NMR(400MHz,DMSO-d6):δ11.12(s,1H),9.37(s,1H),8.64(s,1H),8.50(d,J＝4.0Hz,1H),8.33(d,J＝12.0Hz,1H),8.00(s,1H),7.68–7.60(m,3H),7.34(d,J＝4.0Hz,1H),7.25(dd,J＝8.0Hz,4.0Hz,1H),6.94(d,J＝8.0Hz,1H),5.32(t,J＝4.0Hz,1H),5.07(dd,J＝12.0Hz,8.0Hz,1H),4.20–4.17(m,1H),3.96(s,3H),4.46(s,6H),2.88–2.84(m,1H),2.59–2.54(m,7H),2.43–2.32(m,6H),2.02–1.98(m,1H),1.57–1.49(m,4H),1.38–1.34(m,2H).(M+H)+ 756.6
Synthetic scheme for exemplary Compound 70
2- (2, 6-Dioxopiperidin-3-yl) -5- (2- (2- (2- (2- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) ethoxy) isoindoline-1, 3-dione
Step 1:2- ((1 r,3 r) -3- (benzyloxy) cyclobutoxy) -5-bromopyridine
To a solution of (1 r,3 r) -3- (benzyloxy) cyclobutan-1-ol (500 mg,2.8 mmol) in DMF (15 mL) at 0deg.C was added NaH (336 mg,8.4mmol, 60%). The solution was stirred at 0 ℃ for 30 minutes. A solution of 5-bromo-2-fluoropyridine (1.0 g,5.6 mmol) in DMF (3 mL) was added. The resulting solution was heated at 80 ℃ overnight. After cooling to room temperature, the mixture was quenched with water. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE: ea=100:1) to give the desired compound as a colourless oil (630 mg,67% yield).
Step 2 (1 r,3 r) -3- ((5-bromopyridin-2-yl) oxy) cyclobutan-1-ol
To a solution of 2- ((1 r,3 r) -3- (benzyloxy) cyclobutoxy) -5-bromopyridine (630 mg,1.88 mmol) in DCM (15 mL) at-78℃was added BBr 3 (1.42 g,5.65 mmol). The resulting solution was stirred at-78 ℃ for 0.5 hours. The solution was quenched with NaHCO 3. The layers were separated and the aqueous layer extracted with DCM. The combined organic layers were concentrated to give the desired compound as a yellow solid (390 mg, crude) which was used in the next step without further purification.
Step 3 5-bromo-2- ((1 r,3 r) -3- ((1-phenyl-2, 5,8, 11-tetraoxatridecan-13-yl) oxy) cyclobutoxy) pyridine
To a solution of (1 r,3 r) -3- ((5-bromopyridin-2-yl) oxy) cyclobutan-1-ol (390 mg,1.64 mmol) in THF (15 mL) at 0deg.C was added NaH (262 mg, 60%). The solution was stirred at 10 ℃ for 0.5 hours, then 13-bromo-1-phenyl-2, 5,8, 11-tetraoxatridecane (570 mg,1.64 mmol) was added. The resulting solution was stirred at 70 ℃ for 20 hours. The solution was quenched with water. The layers were separated and the aqueous layer extracted with EA. The combined organic layers were washed with brine. The organic layer was dried over Na 2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel with PE:EA (1:1) to give the desired compound (350 mg) as a yellow solid.
According to the following schemes, and using the above-described procedures and conventional procedures known to those skilled in the art, 5-bromo-2- ((1 r,3 r) -3- ((1-phenyl-2, 5,8, 11-tetraoxatridec-13-yl) oxy) cyclobutoxy) pyridine is converted to the final compound, 2- (2, 6-dioxopiperidin-3-yl) -5- (2- (2- (2- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) ethoxy) isoindoline-1, 3-dione.
Compounds of formula (I) 70：1H NMR(400MHz,DMSO-d6):δ11.10(s,1H),9.36(s,1H),8.62(s,1H),8.50(s,1H),8.31(d,J＝8.2Hz,1H),8.18(d,J＝8.8Hz,1H),7.97(s,1H),7.81(d,J＝8.3Hz,1H),7.60(d,J＝8.0Hz,2H),7.43(s,1H),7.35(d,J＝7.8Hz,1H),6.93(d,J＝8.7Hz,1H),5.31(s,1H),5.11(dd,J＝12.8,5.1Hz,1H),4.31(s,2H),4.22(s,1H),3.95(s,3H),3.79(s,2H),3.64–3.48(m,10H),3.45(d,J＝4.9Hz,3H),2.86(d,J＝13.2Hz,1H),2.45–2.40(m,2H),2.37–2.30(m,2H),2.02(d,J＝6.5Hz,1H).(M+H)+ 778.5.
Synthetic scheme for exemplary Compound 71
2- (2, 6-Dioxopiperidin-3-yl) -5- ((15- (5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) -3,6,9, 12-tetraoxapentadec-14-yn-1-yl) oxy) isoindoline-1, 3-dione
Step 1 15- (5-bromopyridin-2-yl) -3,6,9, 12-tetraoxapentadec-14-yn-1-ol
Then to a solution of 3,6,9, 12-tetraoxapentadecan-14-yn-1-ol (570 mg,2.45 mmol) in anhydrous THF (10 mL) under N 2 atmosphere at 15 ℃ was added 2, 5-dibromopyridine (697.6 mg,2.94 mmol), cuI (51.4 mg,0.27 mmol) and Pd (PPh 3)2Cl2 (80 mg,0.24 mmol). The solution was stirred at 40 ℃ for 1.5 hours, the solution was quenched with H 2 O (10 mL) and the mixture extracted with EtOAc (10 mL x 2).
15- (5-Bromopyridin-2-yl) -3,6,9, 12-tetraoxapentadec-14-yn-1-ol is converted to the final compound, 2- (2, 6-dioxopiperidin-3-yl) -5- ((15- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) -3,6,9, 12-tetraoxapentadec-14-yn-1-yl) oxy) isoindoline-1, 3-dione according to the scheme below and using the procedure described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 71：1H NMR(400MHz,DMSO-d6):δ9.39(s,1H),8.38(d,J＝8.4Hz,1H),8.30(d,J＝2.0Hz,1H),8.28(d,J＝3.0Hz,1H),8.11(s,1H),7.80(d,J＝8.4Hz,1H),7.72(d,J＝7.6Hz,1H),7.63–7.68(m,2H),7.44(d,J＝2.0Hz,1H),7.34–7.36(m,1H),5.08–5.12(m,1H),4.48(s,2H),4.31(t,J＝3.6Hz,2H),3.98(s,3H),3.80(s,3H),3.53–3.79(m,12H),1.95–2.08(m,2H).(M+H)+ 746.5.
Synthetic schemes for exemplary Compound 74
2- (2, 6-Dioxopiperidin-3-yl) -5- ((15- (5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) -3,6,9, 12-tetraoxapentadecyl) oxy) isoindoline-1, 3-dione
Prepared according to the following synthetic schemes using the procedures described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 74：1H NMR(400MHz,CDCl3):δ9.65(s,1H),9.22(s,1H),8.67–8.73(m,2H),8.47(d,J＝7.6Hz,1H),8.36(d,J＝8.0Hz,1H),7.97(s,1H),7.83(s,1H),7.81(s,1H),7.59–7.71(m,2H),7.04(d,J＝9.2Hz,2H),4.93–4.96(m,1H),4.10(s,5H),3.87(s,1H),3.55–3.76(m,18H),3.26(s,2H),2.12–2.16(m,2H).(M+H)+ 750.5.
Synthetic scheme for exemplary Compound 72
5- ((14- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) -4,6, 7-trifluoroisoindoline-1, 3-dione
Prepared according to the following synthetic schemes using the procedures described above and conventional procedures known to those skilled in the art.
2- (2, 6-Dioxopiperidin-3-yl) -4,5, 7-trifluoro-6-hydroxyisoindoline-1, 3-dione was prepared as follows.
Step 1:3,4, 6-trifluoro-5-hydroxyphthalic acid
To a solution of 3,4,5, 6-tetrafluorophthalic acid (1.18 g,5 mmol) in water (20 mL) was added potassium hydroxide (2.24 g,40mmol,8 eq). The resulting solution was heated to 90 ℃ for 9 hours. The reaction was then cooled to room temperature and neutralized with HCl (1N). The resulting solution was extracted with ethyl acetate (50 ml x 3). The combined organic layers were washed with brine (20 ml x 2), dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude desired product (1.15 g) as a white solid which was used in the next step without purification.
Step 2- (2, 6-Dioxopiperidin-3-yl) -4,5, 7-trifluoro-6-hydroxyisoindoline-1, 3-dione
To a solution of 3,4, 6-trifluoro-5-hydroxyphthalic acid (500 mg,2.12 mmol) and 3-aminopiperidine-2, 6-dione (383 mg,2.33 mmol) in AcOH was added AcONa (209 mg,2.54 mmol). The resulting solution was stirred at 120 ℃ for 4 hours. After cooling to room temperature, the solvent was removed under vacuum. It was then quenched with water (30 mL). The resulting solution was extracted with EA (30 mL. Times.3). The combined organic layers were washed with brine (10 ml x 2), dried over anhydrous sodium sulfate and concentrated in vacuo to give 2- (2, 6-dioxopiperidin-3-yl) -4,5, 7-trifluoro-6-hydroxyisoindoline-1, 3-dione (400 mg,1.22mmol, 58%).
Compounds of formula (I) 72：1H NMR(400MHz,CD3OD):δ13.19(s,1H),9.77(s,1H),8.62–8.68(m,2H),8.52(d,J＝8.0Hz,1H),8.16(s,1H),8.01–8.02(m,2H),7.80–7.81(m,1H),7.15–7.28(m,1H),6.99(d,J＝8.0Hz,1H),5.15–5.23(m,1H),4.43–4.45(m,2H),3.77–3.89(m,4H),3.49–3.60(m,12H),2.86–3.05(m,3H),1.99–2.01(m,1H).(M+H)+ 792.5.
Synthetic scheme for exemplary Compound 81
5- ((14- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione
Prepared according to the following synthetic schemes using the procedures described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 81：1H NMR(400MHz,CDCl3):δ9.31(s,1H),8.51(s,1H),8.40(s,1H),8.11(d,J＝8.0Hz,1H),7.82–7.83(m,1H),7.60(s,1H),7.37–7.45(m,3H),6.84(d,J＝8.0Hz,1H),4.92–4.95(m,1H),4.53(t,J＝4.8Hz,2H),4.24(t,J＝4.8Hz,2H),3.89–3.91(m,4H),3.67–3.75(m,12H),2.74–2.92(m,3H),2.12–2.16(m,1H).(M+H)+ 756.5.
Synthetic scheme for exemplary Compound 75
2- (2, 6-Dioxopiperidin-3-yl) -5- (4- (5- ((5- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) pentyl) piperidin-1-yl) isoindoline-1, 3-dione
Prepared according to the following synthetic schemes using the procedures described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 75：1H NMR(400MHz,DMSO-d6):δ＝11.07(s,1H),9.38–9.32(m,1H),8.66–8.63(d,J＝12Hz 1H),8.50–8.48(m,J＝8Hz 1H),8.36(s,2H),8.34–8.29(m,1H),8.21–8.14(m,1H),7.99–7.94(m,1H),7.61(s,3H),7.28–7.22(m,1H),7.19–7.12(m,1H),6.96–6.89(m,1H),5.09–5.00(m,1H),4.36–4.29(m,2H),3.95(s,5H),3.34(s,4H),2.87(s,2H),2.99–2.78(m,1H),2.82–2.73(m,1H),2.04–1.93(m,1H),1.82–1.65(m,4H),1.61–1.52(m,2H),1.52–1.41(m,5H),1.28(s,4H),1.22–1.05(m,4H).(M+H)+ 771.6.
Synthetic scheme for exemplary Compound 76
2- (2, 6-Dioxopiperidin-3-yl) -5- (3- (3- (3- (4- (3- (5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) prop-2-yn-1-yl) piperazin-1-yl) propoxy) azetidin-1-yl) isoindoline-1, 3-dione
Prepared according to the following synthetic schemes using the procedures described above and routine procedures by those skilled in the art.
Compounds of formula (I) 76：1H NMR(400MHz,CD3OD):δ9.32(s,1H),8.96(s,1H),8.45-8.52(m,2H),8.37(d,J＝8.0Hz,1H),8.27-8.31(m,1H),7.98(s,1H),7.61-7.98(m,4H),6.82(s,1H),6.65-6.67(m,1H),5.01-5.05(m,1H),4.59(m,1H),4.27(t,J＝8.4Hz,1H),4.02(s,3H),3.88-3.91(m,2H),3.70(s,2H),3.57(t,J＝6.0Hz,2H),3.41(m,1H),3.13-3.17(m,2H),2.66-2.86(m,11H),2.02-2.03(m,3H).(M+H)+ 751.5.
Synthetic scheme for exemplary Compound 78
2- (2, 6-Dioxopiperidin-3-yl) -5- (4- (6- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) hexyl) piperazin-1-yl) isoindoline-1, 3-dione
Prepared according to the following synthetic schemes using the procedures described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 78：1H NMR(400MHz,DMSO-d6):δ11.08(s,1H),9.35(s,1H),8.64(t,J＝3.9Hz,1H),8.49(d,J＝4.7Hz,1H),8.32(d,J＝8.1Hz,1H),8.19(dd,J＝8.6,2.5Hz,1H),7.98(s,1H),7.68–7.48(m,3H),7.31(d,J＝7.8Hz,1H),7.20(t,J＝9.5Hz,1H),6.94(d,J＝8.6Hz,1H),5.07(dd,J＝12.9,5.3Hz,1H),4.33(t,J＝6.5Hz,2H),3.95(s,3H),3.65(m,1H),3.51–3.41(m,3H),3.36–3.23(m,5H),2.95–2.83(m,1H),2.43–2.28(m,6H),2.05–1.96(m,1H),1.79–1.73(m,1H),1.67–1.61(m,1H),1.42(m,7H).(M+H)+ 770.6.
Synthetic scheme for exemplary Compound 85
2- (2, 6-Dioxopiperidin-3-yl) -5- ((1 r,3 r) -3- ((5- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) pentyl) oxy) cyclobutoxy) isoindoline-1, 3-dione
Prepared according to the following synthetic schemes using the procedures described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 85：1H NMR(400MHz,CDCl3):δ9.32(s,1H),8.58–8.59(d,J＝4.0Hz,2H),8.48(s,1H),8.16–8.18(d,J＝8.0Hz,1H),7.89–7.91(d,J＝8.0Hz,1H),7.74–7.76(d,J＝8.0Hz,1H),7.56(s,1H),7.47–7.49(d,J＝8.0Hz,1H),7.32–7.33(d,J＝4.0Hz,1H),7.19(s,1H),7.06–7.08(d,J＝8.0Hz,1H),6.84–6.86(d,J＝8.0Hz,1H),4.93(m,2H),4.35–4.38(m,2H),4.21(s,1H),3.90(s,3H),3.35–3.49(m,7H),2.68–2.95(m,3H),2.44–2.51(m,4H),2.15(m,1H),1.88(m,2H),1.56–1.68(m,9H),1.44(d,J＝8.0Hz,2H).(M+H)+ 774.6.
Synthetic scheme for exemplary Compound 79
2- (2, 6-Dioxopiperidin-3-yl) -5- (3- ((5- ((5- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) pentyl) oxy) azetidin-1-yl) isoindoline-1, 3-dione)
Prepared according to the following synthetic schemes using the procedures described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 79：1H NMR(400MHz,CDCl3):δ9.35(s,1H),8.59(d,J＝5.7Hz,1H),8.49(s,1H),8.28(s,1H),8.21(d,J＝10.6Hz,1H),8.00(s,1H),7.91(d,J＝11.0Hz,1H),7.63(d,J＝8.2Hz,1H),7.57(s,1H),7.51(d,J＝9.3Hz,1H),7.37(d,J＝5.9Hz,1H),6.85(d,J＝8.6Hz,1H),6.77(s,1H),4.92(m,1H),4.45(s,1H),4.36(t,J＝6.6Hz,2H),4.16–4.26(m,2H),3.83–3.98(m,4H),3.44(m,4H),2.63–2.92(m,3H),2.11(d,J＝6.4Hz,2H),1.79–1.89(m,3H),1.44–1.70(m,10H).(M+H)+ 759.6.
Synthetic scheme for exemplary Compound 80
2- (2, 6-Dioxopiperidin-3-yl) -5- ((1- (5- ((5- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) pentyl) azetidin-3-yl) oxy) isoindoline-1, 3-dione
Prepared according to the following synthetic schemes using the procedures described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 80：1H NMR(400MHz,DMSO-d6):δ11.12(s,1H),9.35(s,1H),8.63(d,J＝2.3Hz,1H),8.50(s,1H),8.31(d,J＝8.1Hz,1H),8.18(dd,J＝8.6,2.5Hz,1H),7.96(s,1H),7.80(d,J＝8.8Hz,1H),7.60(d,J＝6.8Hz,2H),7.23(d,J＝7.2Hz,2H),6.93(d,J＝8.6Hz,1H),5.10(m,1H),5.02–4.95(m,1H),4.32(t,J＝6.6Hz,2H),3.95(s,3H),3.70(t,J＝6.8Hz,2H),2.99–2.95(m,2H),2.86(d,J＝12.1Hz,2H),2.64(br,1H),2.55(br,2H),2.33(s,2H),2.06–1.96(m,3H),1.81–1.70(m,3H),1.60–1.40(m,8H).(M+H)+ 759.6.
Synthetic scheme for exemplary Compound 84
2- (2, 6-Dioxopiperidin-3-yl) -5- ((6- (3- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) phenoxy) hexyl) oxy) isoindoline-1, 3-dione
Step 1:2- ((6- (3- (benzyloxy) phenoxy) hexyl) oxy) tetrahydro-2H-pyran
A solution of 3- (benzyloxy) phenol (1.13 g,5.66 mmol), 2- ((6-bromohexyl) oxy) tetrahydro-2H-pyran (1.0 g,3.77 mmol) and Cs 2CO3 (2.45 g,7.55 mmol) in acetone was stirred (30 mL) at 70℃overnight. The mixture was cooled to room temperature and quenched with water. The mixture was extracted with EA (200 mL) and the solution was washed with water (30 mL x 3) and brine (30 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified to give the desired product (PE: ea=20:1) (1.2 g, yield=83%).
Step 2:3- ((6- ((tetrahydro-2H-pyran-2-yl) oxy) hexyl) oxy) phenol
To a solution of 2- ((6- (3- (benzyloxy) phenoxy) hexyl) oxy) tetrahydro-2H-pyran (1.2 g,3.13 mmol) in MeOH (30 mL) at room temperature was added Pd/C (200 mg). The resulting solution was stirred at room temperature under H 2 atm overnight. The mixture was filtered and the filtrate concentrated in vacuo to give the crude desired product (900 mg) as a pale yellow oil, which was used directly in the next step.
Step 3 2- ((6- (3- ((1 r,3 r) -3- (benzyloxy) cyclobutoxy) phenoxy) hexyl) oxy) tetrahydro-2H-pyran
To a solution of 3- ((6- ((tetrahydro-2H-pyran-2-yl) oxy) hexyl) oxy) phenol (100 mg,0.34 mmol), (1 s,3 s) -3- (benzyloxy) cyclobutanol (91 mg,0.51 mmol), PPh 3 (267 mg,1.02 mmol) in THF (5.0 mL) at 40℃under nitrogen atmosphere was added DIAD (206 mg,1.02 mmol). The resulting mixture was heated to 80 ℃ overnight. After cooling to room temperature, the reaction was quenched with water. The mixture was extracted with EA (50 mL), and the organic phase was washed with water (20 mL x 3), brine (20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified to give the desired product (PE: ea=5:1) (130 mg, yield=84%) as a colorless oil.
2- ((6- (3- ((1 R,3 r) -3- (benzyloxy) cyclobutoxy) phenoxy) hexyl) oxy) tetrahydro-2H-pyran is converted to the final compound, 2- (2, 6) -dioxopiperidin-3-yl) -5- ((6- (3- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) phenoxy) hexyl) oxy) isoindoline-1, 3-dione, according to the following synthetic scheme, using the procedure described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 84：1H NMR(400MHz,CDCl3):δ93.4(s,1H),8.58(d,J＝5.6Hz,1H),8.21-8.48(m,2H),8.20(d,J＝8.4Hz,1H),7.88-7.91(m,1H),7.76(d,J＝8.4Hz,1H),7.56(s,1H),7.51(d,J＝8.0Hz,1H),7.33-7.36(m,2H),7.16-7.18(m,2H),6.86(d,J＝8.4Hz,1H),6.39-6.51(m,3H),5.52-5.54(m,1H),4.94-4.96(m,2H),4.07-4.10(m,2H),3.91-3.97(m,5H),3.22-3.24(m,1H),2.69-2.76(m,7H),2.14-2.16(m,1H),1.82-1.86(m,4H),1.54-1.57(m,4H).(M+H)+ 794.5.
Synthetic scheme for exemplary Compound 86
4- ((14- (4- (5H-pyrido [4,3-b ] indol-7-yl) phenoxy) -3,6,9, 12-tetraoxatetradecyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
Prepared according to the following synthetic schemes using the procedures described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 86：1H NMR(400MHz,CDCl3):δ9.28(s,2H),8.50(s,1H),8.08(s,1H),7.35－7.57(m,6H),6.94－6.96(m,3H),6.77(s,1H),6.38(s,1H),4.88－4.90(m,1H),4.14(s,2H),3.60－3.86(m,17H),3.31－3.34(m,2H),2.66－2.86(m,3H),2.03－2.05(m,1H).(M+H)+ 736.5.
Synthetic scheme for exemplary Compound 87
6- ((14- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) -1H-pyrrolo [3,4-c ] pyridine-1, 3 (2H) -dione
Step 1:6- ((14- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) pyridine-3, 4-dicarboxylic acid
To a solution of 14- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecan-1-ol (200.0 mg,0.42 mmol) and 6-chloropyridine-3, 4-dicarboxylic acid (166 mg,0.83 mmol) in dry tetrahydrofuran (4 mL) was added sodium hydride (162.0 mg,4.2 mmol). The resulting solution was stirred with MW at 100℃for 2 hours under N 2 atmosphere. The solution was cooled to room temperature and quenched with water (20 mL). The mixture was extracted with ethyl acetate (20 mL. Times.3). The combined organic layers were washed with brine (20 ml×2). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the desired compound (50 mg,0.077mmol,9% yield).
Step 2:6- ((14- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) -1H-pyrrolo [3,4-c ] pyridine-1, 3 (2H) -dione
To a solution of 6- ((14- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3,6,9,12 in solution-tetraoxatetradecyl) oxy) pyridine-3, 4-dicarboxylic acid (50 mg,0.077 mmol) and 3-aminopiperidine-2, 6-dione (12 mg,0.092 mmol) in AcOH (6 mL) was added NaOAc (6 mg,0.092 mmol). The resulting solution was stirred at 120 ℃ for 16 hours. After cooling to room temperature, the reaction was quenched by the addition of water (20 mL). The mixture was extracted with EA (20 ml x 3). The combined organic layers were washed with brine (20 ml x 2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC using DCM/CH 3 OH (10:1) to give the title compound (4.0 mg,0.005mmol,7% yield).
Compounds of formula (I) 87：1H NMR(400MHz,CDCl3):δ9.28(s,1H),8.42(s,1H),8.37–8.39(m,2H),8.06(d,J＝8.0Hz,1H),7.80(d,J＝8.0Hz,1H),7.62(s,1H),7.40–7.45(m,3H),6.09(s,1H),6.82(d,J＝8.8Hz,1H),4.94–4.99(m,1H),4.54(t,J＝4.8Hz,4H),3.86–3.91(m,4H),3.66–3.75(m,12H),2.73–2.92(m,3H),2.20–2.22(m,1H).(M+H)+ 739.5.
Synthetic scheme for exemplary Compound 88
2- (2, 6-Dioxopiperidin-3-yl) -5- ((14- ((5- (5- (2, 2-trifluoroethyl) -5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) isoindoline-1, 3-dione
Prepared according to the following synthetic schemes using the procedures described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 88：1H NMR(400MHz,CDCl3):δ9.35(s,1H),8.63(d,J＝7.6Hz,1H),8.45(s,1H),8.21(d,J＝8.0Hz,1H),8.16(s,1H),7.87–7.90(m,1H),7.75(d,J＝8.4Hz,1H),7.53–7.58(m,2H),7.39(s,1H),7.35(s,1H),7.21(d,J＝8.4Hz,1H),6.91(d,J＝8.8Hz,1H),4.87–4.92(m,3H),4.55(t,J＝4.8Hz,2H),4.24(t,J＝4.8Hz,2H),3.90(t,J＝4.4Hz,3H),3.66–3.73(m,12H),2.76–2.87(m,3H),2.09–2.16(m,1H).(M+H)+ 820.5
Synthetic scheme for exemplary Compound 89
2- (2, 6-Dioxopiperidin-3-yl) -5- (4- (3, 3-trifluoro-2- (2- ((5- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin-2-yl) oxy) pentyl) oxy) ethoxy) piperidin-1-yl) isoindoline-1, 3-dione
Step1 2- (5-Benzyloxypentyloxy) acetic acid ester
To a solution of 5-benzyloxypentan-1-ol (1 g,5.15mmol,1.0 eq.) in dichloromethane (20 mL) was added ethyl 2-diazoacetate (704 mg,6.18mmol,1.2 eq.) and disodium tetraacetate (11 mg,0.03 mmol). The mixture was then stirred at 20 ℃ for 0.5 hours. The mixture was quenched with ethanol (10 mL) and then concentrated. The residue was purified by silica column chromatography (petroleum ether; ethyl acetate=50:1 to 4:1) to give ethyl 2- (5-benzyloxypentyloxy) acetate (700 mg,2.50mmol,49% yield) as a yellow oil.
Step 2- (5-Benzyloxypentyloxy) ethanol
To a mixture of LiAlH 4 (189 mg,4.99mmol,2.0 eq.) in tetrahydrofuran (4 mL) was added a solution of ethyl 2- (5-benzyloxypentyloxy) acetate (700 mg,2.50mmol,1.0 eq.) in tetrahydrofuran (10 mL) at 0 ℃. The mixture was then stirred at 20 ℃ for 2 hours. The mixture was quenched with water (0.2 mL), aqueous sodium hydroxide (1 m,0.2 mL) and more water (0.8 mL). Then filtered and concentrated. The residue was purified by silica column chromatography (petroleum ether: ethyl acetate=30:1 to 10:1) to give 2- (5-benzyloxypentyloxy) ethanol (400 mg,1.68mmol,67% yield) as a white oil.
Step 3 2- (5-Benzyloxypentyloxy) ethyl 4-methylbenzenesulfonate
To a mixture of 2- (5-benzyloxypentyloxy) ethanol (400 mg,1.68mmol,1.0 eq.) and tosyl chloride (640 mg,3.36mmol,2.0 eq.) in tetrahydrofuran (3 mL) was added potassium hydroxide (2.83 g,50.35mmol,30.0 eq.). The mixture was then stirred at 20 ℃ for 0.5 hours. The mixture was diluted with water (10 mL), extracted with ethyl acetate (20 mL), washed with brine (20 mL), dried over anhydrous sodium sulfate, and then concentrated. The mixture was purified by silica column chromatography (petroleum ether: ethyl acetate=30:1 to 10:1) to give 2- (5-benzyloxypentyloxy) ethyl-4-methylbenzenesulfonate (570 mg,1.45mmol,86% yield) as a white oil.
Step 4 t-butyl 4- (3, 3-trifluoro-2-hydroxy-propyl) piperidine-1-carboxylate
To a mixture of tert-butyl 4- (2-oxoethyl) piperidine-1-carboxylate (1.9 g,8.36mmol,1.0 eq.) and trimethyl (trifluoromethyl) silane (1.43 g,10.03mmol,1.2 eq.) in tetrahydrofuran (20 mL) was added tetrabutylammonium fluoride (1M, 0.1 mL) at 0deg.C. The mixture was then stirred at 20 ℃ for 1 hour. Aqueous hydrochloric acid (1 m,17ml,2.0 eq) was then added to the mixture and stirred at 20 ℃ for an additional 2 hours. The mixture was extracted with dichloromethane (100 mL), washed with brine (50 mL), dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by silica column chromatography (petroleum ether: ethyl acetate=100:1 to 10:1) to give tert-butyl 4- (3, 3-trifluoro-2-hydroxy-propyl) piperidine-1-carboxylate (2.0 g,6.73mmol,80% yield) as a white solid.
Step 5 tert-butyl 4- [2- [2- (5-Benzyloxypentyloxy) ethoxy ] -3, 3-trifluoro-propyl ] piperidine-1-carboxylate
To a solution of tert-butyl 4- (3, 3-trifluoro-2-hydroxy-propyl) piperidine-1-carboxylate (216 mg,0.73mmol,1.0 eq.) in dimethylformamide (2 mL) was added sodium hydride (58 mg,1.46mmol, 60% in mineral oil, 2.0 eq.) at 15 ℃. The mixture was then stirred under nitrogen at 15 ℃ for 0.5 hours. 2- (5-Benzyloxypentyloxy) ethyl 4-methylbenzenesulfonate (200 mg,0.51mmol,0.7 eq.) was added to the mixture and stirred at 50℃for an additional 2.5 hours. The mixture was quenched with water (5 mL), extracted with ethyl acetate (20 mL x 2), washed with brine (20 mL), dried over anhydrous sodium sulfate, and then concentrated. The mixture was purified by silica column chromatography (petroleum ether: ethyl acetate=200:1 to 10:1) to give tert-butyl 4- [2- [2- (5-benzyloxypentyloxy) ethoxy ] -3, 3-trifluoro-propyl ] piperidine-1-carboxylate (300 mg,0.58mmol,80% yield) as a white oil.
Tert-butyl 4- [2- [2- (5-benzyloxy-pentyloxy) ethoxy ] -3, 3-trifluoro-propyl ] piperidine-1-carboxylate was converted to the title compound, 2- (2, 6-dioxopiperidin-3-yl) -5- (4- (3, 3-trifluoro-2- (2- ((5- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) pentyl) oxy) propyl) piperidin-1-yl) isoindoline-1, 3-dione, according to the following synthetic scheme, using the procedure described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 89：1H NMR(400MHz,DMSO-d6)δ:11.09(s,1H),9.36(s,1H),8.61(d,J＝2.4Hz,1H),8.50(d,J＝5.6Hz,1H),8.31(d,J＝8.0Hz,1H),8.21(s,1H),8.15(dd,J＝2.8,8.8Hz,1H),7.95(s,1H),7.65–7.57(m,3H),7.29(s,1H),7.23–7.18(m,1H),6.90(d,J＝8.8Hz,1H),5.04(dd,J＝5.6,12.8Hz,1H),4.31(t,J＝6.4Hz,2H),4.14(br s,1H),4.10–3.99(m,3H),3.96(s,3H),3.87(d,J＝11.6Hz,2H),3.74(dd,J＝5.6,10.8Hz,2H),3.02–2.81(m,4H),1.98–1.86(m,2H),1.85–1.72(m,4H),1.63–1.15(m,9H).(M+H)+ 841.6.
Synthetic scheme for exemplary Compound 90
2- (2, 6-Dioxopiperidin-3-yl) -5- (4- (4- ((4- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) but-2-yn-1-yl) oxy) butoxy) isoindoline-1, 3-dione
Prepared according to the following synthetic schemes using the procedures described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 90：1HNMR(400MHz,CDCl3):δ9.35(s,1H),8.60(s,1H),8.50(s,1H),8.20(d,J＝8.0Hz,2H),7.75(d,J＝8.0Hz,1H),7.55(s,1H),7.49(d,J＝8.0Hz,1H),7.32(d,J＝10.0Hz,2H),7.16(d,J＝8.0Hz,1H),6.92(d,J＝8.4Hz,1H),5.10(s,2H),4.98-5.00(m,1H),4.21(s,2H),4.07-4.10(m,2H),3.90(s,3H),3.44-3.54(m,7H),2.76-2.87(m,3H),2.18-2.23(m,2H),1.88-1.92(m,3H),1.72-1.75(m,4H).M+H)+ 744.5.
Synthetic scheme for exemplary Compound 91
2- (2, 6-Dioxopiperidin-3-yl) -5- (4- (8- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) octyl) piperazin-1-yl) isoindoline-1, 3-dione
Prepared according to the following synthetic schemes using the procedures described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 91：1H NMR(400MHz,CD3OD):δ9.33(s,1H),8.51-8.53(m,2H),8.33-8.34(m,1H),8.09-8.11(m,1H),7.84(s,1H),7.59-7.62(m,3H),7.30(s,1H),7.17(d,J＝8.4Hz,1H),6.90(d,J＝8.4Hz,1H),5.32-5.35(m,1H),3.99(s,3H),3.40-3.47(m,13H),2.69-2.71(m,6H),2.50-2.52(m,4H),2.03-2.18(m,5H),1.59-1.60(m,6H).(M+H)+ 798.6.
Synthetic schemes for exemplary Compound 92
5- ((14- ((3-Chloro-5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
Prepared according to the following synthetic schemes using the procedures described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 92：1H NMR(400MHz,CDCl3):δ9.32(s,1H),8.68(s,1H),8.58(s,1H),8.35(s,1H),8.18(d,J＝8.0Hz,1H),7.97(s,1H),7.74(d,J＝8.4Hz,1H),7.52(s,1H),7.45(d,J＝8.0Hz,1H),7.27－7.34(m,2H),7.20(d,J＝7.6Hz,1H),4.92－4.96(m,1H),4.61(s,2H),4.23(s,2H),3.89－3.94(m,8H),3.68－3.78(m,11H),2.72－2.90(m,3H),2.01－2.12(m,1H).(M+H)+ 786.5,788.5.
Synthetic scheme for exemplary Compound 93
5- ((6- ((5- (2, 2-Difluoro-2- (5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) ethoxy) pentyl) oxy) hexyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
Prepared according to the following synthetic schemes using the procedures described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 93：1H NMR(400MHz,CDCl3):δ9.35(br,1H),8.94(s,1H),8.59(s,1H),8.21(d,J＝8.0Hz,1H),8.01-8.09(m,2H),7.73(d,J＝8.4Hz,1H),7.69(d,J＝8.0Hz,1H),7.58(s,1H),7.51(d,J＝8.4Hz,1H),7.31(d,J＝5.2Hz,1H),7.24(s,1H),7.09(dd,J＝8.0,2.0Hz,1H),4.85-4.90(m,1H),4.10(t,J＝8.0Hz,1H),3.98(t,J＝6.4Hz,1H),3.87(s,3H),3.51(t,J＝6.4Hz,1H),3.27-3.32(m,4H),2.65-2.85(m,3H),2.04-2.08(m,1H),1.71-1.76(m,4H),1.45-1.52(m,8H),0.75-0.85(m,4H).(M+H)+ 782.5.
Synthetic scheme for exemplary Compound 96
2- (2, 6-Dioxopiperidin-3-yl) -5- (4- (6- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) hexyl) -3- (trifluoromethyl) piperazin-1-yl) isoindoline-1, 3-dione
Prepared according to the following synthetic schemes using the procedures described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 96：1H NMR:400MHz,DMSO-d6δ:11.09(s,1H),9.38(s,1H),8.64(d,J＝2.4Hz,1H),8.51(d,J＝5.6Hz,1H),8.33(d,J＝8.0Hz,1H),8.19(dd,J＝2.4,8.8Hz,1H),8.14(s,1H),7.99(s,1H),7.72–7.59(m,3H),7.21(d,J＝2.0Hz,1H),7.12(dd,J＝2.0,8.8Hz,1H),6.94(d,J＝8.4Hz,1H),5.38–5.26(m,1H),5.06(dd,J＝5.3,12.9Hz,1H),4.24–4.13(m,1H),3.96(s,3H),3.95–3.88(m,1H),3.72(d,J＝15.2Hz,1H),3.68–3.63(m,1H),3.53(d,J＝7.2Hz,1H),3.31(s,2H),3.07–2.75(m,4H),2.74–2.54(m,4H),2.44–2.29(m,4H),2.06–1.94(m,1H),1.50(td,J＝7.0,13.8Hz,4H),1.33(s,4H).(M+H)+ 838.6.
Synthetic scheme for exemplary Compound 99
2- (2, 6-Dioxopiperidin-3-yl) -5- ((1- (3- (3- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) propoxy) propyl) azetidin-3-yl) oxy) isoindoline-1, 3-dione
Step 1 2- (3-bromopropyloxy) tetrahydro-2H-pyran
A mixture of 3-bromopropan-1-ol (5.56 g,40 mmol), dihydropyran (4.0 g,48 mmol) and p-toluenesulfonic acid (0.76 g,4 mmol) in tetrahydrofuran (80 ml) was stirred at room temperature overnight. The reaction mixture was quenched with aqueous sodium bicarbonate (saturated 10 ml) and extracted with tert-butyl methyl ether (50 ml x 3). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluting with 10% ethyl acetate in hexane) to give 2- (3-bromopropyloxy) tetrahydro-2H-pyran (6.4 g, yield 72%) as a colorless oil.
Step 2 3- (3- ((tetrahydro-2H-pyran-2-yl) oxy) propoxy) propan-1-ol
To a solution of propane-1, 3-diol (4.6 g,60 mmol) in N, N-dimethylformamide (50 ml) was added sodium hydride (60% in mineral oil) (0.88 g,222 mmol) at 0℃and the resulting mixture was stirred at 0℃for 30 minutes. 2- (3-bromopropyloxy) tetrahydro-2H-pyran (2.2 g,20 mmol) was added to the reaction mixture, and the resulting reaction mixture was stirred at 65℃for 16 hours. The reaction mixture was quenched with water (150 ml) at 0 ℃ and extracted with ethyl acetate (200 ml x 2). The combined organic layers were washed with brine (50 ml x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (eluting with 30% ethyl acetate in hexane) to give 3- (3- ((tetrahydro-2H-pyran-2-yl) oxy) propoxy) propan-1-ol as a colourless oil (0.9 g, 45% yield).
Step 3- (3- ((tetrahydro-2H-pyran-2-yl) oxy) propoxy) propyl 4-methylbenzenesulfonate
To a stirred solution of 3- (3- ((tetrahydro-2H-pyran-2-yl) oxy) propoxy) propan-1-ol (900 mg,4.1 mmol), triethylamine (1.1 ml,8.25 mmol) in dichloromethane (30 ml) at 0℃was added tosyl chloride (0.94 g,4.95 mmol) and 4-dimethylaminopyridine (50 mg,0.4 mmol). The resulting solution was allowed to warm to room temperature and stirred at room temperature for 2 hours. The mixture was poured into water (20 ml) and extracted with dichloromethane (20 ml x 2). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash column chromatography (eluting with 10-20% ethyl acetate in hexane) to give 3- (3- ((tetrahydro-2H-pyran-2-yl) oxy) propoxy) propyl 4-methylbenzenesulfonate (1.2 g, yield 78%) as a colorless oil.
Step 4 2- (3- (3- ((1 r,3 r) -3- (benzyloxy) cyclobutoxy) propoxy) tetrahydro-2H-pyran
To a solution of (1 r,3 r) -3- (benzyloxy) cyclobutanol (200 mg,1.12 mmol) in N, N-dimethylformamide (6 ml) was added sodium hydride (60% in mineral oil) (63 mg,1.57 mmol) at 0℃and the resulting mixture was stirred at room temperature for 30 min. 3- (3- ((tetrahydro-2H-pyran-2-yl) oxy) propoxy) propyl 4-methylbenzenesulfonate (501 mg,1.34 mmol) was added and the resulting reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (30 ml) at 0 ℃ and extracted with ethyl acetate (60 ml x 2). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (eluting with 30% ethyl acetate in hexane) to give 2- (3- (3- ((1 r,3 r) -3- (benzyloxy) cyclobutoxy) propoxy) tetrahydro-2H-pyran (234 g, yield 47%) as a colourless oil.
Step 5 (1 r,3 r) -3- (3- (3-hydroxypropoxy) propoxy) cyclobutanol
A mixture of 2- (3- (3- ((1 r,3 r) -3- (benzyloxy) cyclobutoxy) propoxy) tetrahydro-2H-pyran (4638 g,1.23 mmol), palladium on carbon (10%, 60 mg) in methanol (30 ml) was stirred under hydrogen atmosphere (hydrogen balloon) at room temperature overnight. Palladium on carbon was removed by filtration and washed with methanol (5 ml x 2). The combined filtrates were concentrated under reduced pressure to give (1 r,3 r) -3- (3- (3-hydroxypropoxy) propoxy) cyclobutanol as a colorless oil (240 mg, yield: 95%).
Step 6 3- (3- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) propan-1-ol
To a solution of (1 r,3 r) -3- (3- (3-hydroxypropoxy) propoxy) cyclobutanol (100 mg,0.49 mmol) in N, N-dimethylformamide (3 ml) was added sodium hydride (60% in mineral oil) (28 mg,0.69 mmol), and the resulting mixture was stirred at room temperature for 30 minutes. 7- (6-Fluoropyridin-3-yl) -5-methyl-5H-pyrido [4,3-b ] indole (96 mg,0.35 mmol) was added and the resulting reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water (30 ml) at 0 ℃ and extracted with ethyl acetate (60 ml x 2). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (eluting with 5% methanol in dichloromethane) to give 3- (3- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) propan-1-ol as a white solid (75 mg, 34% yield).
Step 7 3- (3- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) propoxy) propanal
To a stirred solution of 3- (3- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) propoxy) propan-1-ol (70 mg,0.15 mmol) in dichloromethane (5 ml) was added Dess-Martin periodate (Dess-Martin periodinane) (129 mg,0.3 mmol) at 0 ℃. The resulting reaction mixture was allowed to warm to room temperature and stirred at this temperature for an additional 30 minutes. The reaction mixture was quenched with aqueous sodium bicarbonate (10 ml) and extracted with dichloromethane (20 ml x 2), washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude 3- (3- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) propanal (80 mg, crude) as a white solid, which was used in the next step without further purification.
Step 8 2- (2, 6-Dioxopiperidin-3-yl) -5- ((1- (3- (3- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) propoxy) azetidin-3-yl) oxy) isoindoline-1, 3-dione
A mixture of 5- (azetidin-3-yloxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione hydrochloride (70 mg,0.17 mmol) [ prepared using the procedure described above and conventional procedures known to those skilled in the art, as shown in the schemes below ], N-ethyl-N-isopropyl-2-amine (44 mg,0.35 mmol), acetic acid (1 drop) and 3- (3- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) propoxy) propanal (80 mg, 0.17) in methanol (5 ml) was stirred at room temperature for 30 minutes followed by addition of sodium cyanoborohydride (22 mg,0.35 mmol) at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with aqueous sodium bicarbonate (saturated 10 ml) and extracted with ethyl acetate (20 ml), washed with brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified by preparative TLC (eluting with 10% methanol in dichloromethane) to give 2- (2, 6-dioxopiperidin-3-yl) -5- ((1- (3- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) propyl) azetidin-3-yl) oxy) isoindoline-1, 3-dione (20 mg, yield: 15%) as a white solid.
Compounds of formula (I) 99：1H NMR(400Hz,DMSO-d6):δ1.40-1.56(m,2H),1.62-1.75(m,2H),1.83-2.09(m,2H),2.34-2.50(m,3H),2.58-2.73(m,2H),2.83-2.93(m,1H),3.01-3.13(m,2H),3.37-3.52(m,8H),3.77(s,2H),3.95(s,3H),4.18(s,1H),5.02-5.13(m,2H),5.29-5.37(m,1H),6.94(d,J＝8.0Hz,1H),7.21-7.29(m,2H),7.59-7.65(m,2H),7.80(d,J＝7.2Hz,1H),7.97(s,1H),8.18(d,J＝7.6Hz,1H),8.31(d,J＝7.6Hz,1H),8.50(d,J＝5.2Hz,1H),8.63(s,1H),9.35(s,1H),11.11(s,1H).(M+H)+ 773.5.
Synthetic scheme for exemplary Compound 100
2- (2, 6-Dioxopiperidin-3-yl) -5- (6- (4- (4- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) butoxy) -2-aza-spiro [3.3] heptane-2-yl) isoindoline-1, 3-dione
Prepared according to the following synthetic schemes using the procedures described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 100：1H NMR(400MHz,CDCl3):δ1.65-1.67(m,6H),1.74-1.81(m,2H),1.87-1.94(m,2H),2.00-2.06(m,1H),2.09-2.14(m,1H),2.18-2.24(m,2H),2.54-2.59(m,2H),2.68-2.90(m,3H),3.37-3.53(m,5H),3.91(t,J＝7.6Hz,3H),3.98(d,J＝8.0Hz,3H),4.39(t,J＝6.4Hz,2H),4.90-4.94(m,1H),6.45(d,J＝1.6Hz,1H),6.72(d,J＝1.6Hz,1H),6.85(d,J＝8.4Hz,1H),7.35(d,J＝6Hz,1H),7.50(d,J＝8.0Hz,1H),7.56(s,1H),7.61(d,J＝8.0Hz,1H),7.91(d,J＝2.4Hz,1H),8.05(s,1H),8.21(d,J＝8.0Hz,1H),8.49(d,J＝2.4Hz,1H),8.60(d,J＝5.6Hz,1H),9.34(s,1H).(M+H)+ 771.6.
Synthetic scheme for exemplary Compound 101
5- ((1- (3- (3- ((1 R,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) -3- (trifluoro-yl) pyridin-2-yl) oxy) cyclobutoxy) propoxy) propyl) azetidin-3-yl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
Prepared according to the following synthetic schemes using the procedures described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 101：1H NMR(400Hz,D6-DMSO):δ1.56-1.59(m,2H),1.71-1.77(m,2H),1.95-2.05(m,2H),2.34-2.46(m,3H),2.50-2.67(m,3H),2.83-2.93(m,1H),3.32-3.49(m,9H),3.88-3.92(m,1H),4.17-4.20(m,1H),4.55(t,J＝5.6Hz,1H),5.05-5.13(m,2H),5.46-5.49(m,1H),7.25-7.28(m,2H),7.52(d,J＝5.6Hz,1H),7.63(d,J＝8.0Hz,1H),7.82(d,J＝8.0Hz,1H),7.87(s,1H),8.33(d,J＝8.0Hz,1H),8.39(s,1H),8.45(d,J＝6.0Hz,1H),8.83(s,1H),9.39(s,1H),11.11(s,1H),11.86(s,1H).(M+H)+ 827.5.
Using a similar procedure, compound 105 was prepared.
Synthetic scheme for exemplary Compound 103
5- ((14- ((5- (8, 9-Difluoro-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxymethyl) -3,6,9, 12-tetraoxatetradecyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
Step 1 5-bromo-2- ((1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl) oxy) pyridine
To a solution of the compound 5-bromo-2-fluoropyridine (2.0 g,9.5 mmol) in DMF (20 mL) was added 1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-ol (2.6 g,7.91 mmol) and NaH (950 mg,24mmol, 60%). The resulting mixture was stirred at 20 ℃ for 18 hours. TLC (PE: ea=1:1, rf=0.5) showed that 5-bromo-2-fluoropyridine was consumed. The mixture was diluted with EA (30 mL), washed with water (3 x 30 mL) and brine (30 mL). The organic layer was dried and concentrated to give a crude product which was purified by column chromatography on silica gel with PE:EA (1:1) to give the desired product (3.6 g) as a colourless oil.
Step 2- ((1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl) oxy) -5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridine
To a solution of 5-bromo-2- ((1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl) oxy) pyridine (3.6 g,7.22 mmol) in dioxane (50 mL) was added 4,4', 5' -octamethyl-2, 2' -bis (1, 3, 2-dioxaborane) (3.7 g,14.45 mmol), pd (dppf) Cl 2 (530 mg) and AcOK (1.42 g,14.45 mmol). The resulting solution was stirred at 90 ℃ for 18 hours. The mixture was filtered and concentrated. The crude product was purified by column chromatography on silica gel with pe:ea (1:1) to give the desired product as a yellow oil (3.0 g, yield = 78%).
Step 3 5- (4-bromo-2, 3-difluorophenyl) -2- ((1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl) oxy) pyridine
To a solution of 2- ((1-phenyl-2,5,8,11,14-pentaoxahexadec-16-yl) oxy) -5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (2.8 g,5.27 mmol)) in dioxane/H 2 O (55 mL,10/1, v/v) was added 1, 4-dibromo-2, 3-difluorobenzene (1.72 g,6.32mmol, csF (1.6 g,10.54 mmol) and Pd (PPh 3) (300 mg). The resulting solution was stirred at 90 ℃ for 18 hours under N 2. After the reaction was completed, the mixture was quenched with EA and extracted with EA. The organic layer was washed with brine, dried over Na 2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel with pe:ea (1:1) to give the desired product as a brown oil (1.5 g, yield = 48%).
Step 45- (2, 3-difluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -2- ((1-phenyl) -2,5,8,11,14-pentaoxahexadecan-16-yl) oxy) pyridine
To a solution of 5- (4-bromo-2, 3-difluorophenyl) -2- ((1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl) oxy) pyridine (1.0 g,1.68 mmol) in dioxane (20 mL) was added 4,4', 5' -octamethyl-2, 2' -bis (1, 3, 2-dioxaborane) (640 mg,2.52 mmol), pd (dppf) Cl 2 (120 mg) and AcOK (330 mg,3.36 mmol). The resulting solution was stirred at 90 ℃ for 18 hours. LCMS showed complete consumption of 5- (4-bromo-2, 3-difluorophenyl) -2- ((1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl) oxy) pyridine. The mixture was filtered and concentrated. The crude product was purified by column chromatography on silica gel with pe:ea (3:2) to give the desired product as a brown oil (660 mg, yield = 95%).
Step 5- (2, 3-difluoro-4- (4-nitropyridin-3-yl) phenyl) -2- ((1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl) oxy) pyridine
To a solution of 5- (2, 3-difluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -2- ((1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl) oxy) pyridine (350 mg,0.544 mmol) in dioxane/H 2 O (11 mL,10/1, v/v) was added 3-bromo-4-nitropyridine (121 mg,0.6 mmol), na 2CO3 (120 mg,1.1 mmol) and Pd (PPh 3)4 (63 mg.) after stirring the mixture at N 2 Under at 110 ℃ for 1 hour, the mixture was extracted with ethyl acetate (20 mL) and washed with brine (30 mL), the organic solution was dried over anhydrous sodium sulfate and concentrated.
Step 6, 8, 9-difluoro-7- (6- ((1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl) oxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole
A solution of 5- (2, 3-difluoro-4- (4-nitropyridin-3-yl) phenyl) -2- ((1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl) oxy) pyridine (340 mg,0.53 mmol) in P (Oet) 3 (3 mL) was stirred at 110℃for 3 hours. After the reaction, the mixture was purified by column chromatography on silica gel with DCM/MeOH (30:1) to give the desired product (205 mg) as a brown solid.
According to the following synthetic schemes, 8, 9-difluoro-7- (6- ((1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl) oxy) pyridin-3-yl) -5H-pyrido [4,3-b ] indole was prepared using the procedure described above and conventional procedures known to those skilled in the art
To the final compound, 5- ((14- ((5- (8, 9-difluoro-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (compound 103), and 5- ((14- ((5- (8, 9-difluoro-5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (compound 112).
Compounds of formula (I) 103：1H NMR(400MHz,CD3OD):δ9.46(s,1H),8.63(d,J＝6.8Hz,1H),8.38(s,1H),8.00(d,J＝6.8Hz,1H),7.96(d,J＝8.8Hz,1H),7.67(d,J＝8.4Hz,1H),7.61(d,J＝4.8Hz,1H),7.29(s,1H),7.23(d,J＝8.4Hz,1H),6.93(d,J＝8.8Hz,1H),5.05(m,1H),4.54–4.45(m,2H),4.26–4.19(m,2H),3.86(m,4H),370-3.65(m,12H),2.86–2.62(m,3H),2.10–2.04(m,1H).(M+H)+774.5.
Compounds of formula (I) 112：1HNMR(400MHz,CDCl3):δ:11.09(s,1H),9.25(s,1H),8.50(s,1H),8.59(s,1H),8.07(d,J＝8.4Hz,1H),7.79(d,J＝8.4Hz,1H),7.69-7.73(m,2H),7.75(d,J＝8.4Hz,1H),7.42(s,1H),7.34(d,J＝8.4Hz,1H),7.02(d,J＝8.4Hz,1H),5.08-5.13(m,1H),4.46(d,J＝4.4Hz,2H),4.30-4.34(m,2H),3.95(s,3H),3.79(s,4H),3.60(s,4H),3.56(s,4H),3.53(s,4H),2.85-2.88(m,1H),2.61(s,2H).(M+H)+ 788.5.
Synthetic schemes for exemplary Compound 104
2- (2, 6-Dioxopiperidin-3-yl) -5- (3- (3- (3- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) propoxy) azetidin-1-yl) isoindoline-1, 3-dione
Prepared according to the following synthetic schemes using the procedures described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 104：1H NMR(400MHz,DMSO-d6):δ1.73-1.79(m,4H),1.97-1.99(m,2H),2.31-2.37(m,2H),2.40-2.49(m,2H),2.54-2.59(m,1H),2.83-2.88(m,1H),3.38(t,J＝6.4Hz,2H),3.43-3.49(m,6H),3.82-3.85(m,2H),3.75(s,3H),4.16-4.18(m,1H),4.20-4.26(m,2H),4.43-4.47(m,1H),5.02-5.07(m,1H),5.31-5.34(m,1H),6.62-6.64(m,1H),6.78-6.79(m,1H),6.93(t,J＝8.4Hz,1H),7.59-6.72(m,3H),7.96(s,1H),8.17-8.19(m,1H),8.30(d,J＝8.0Hz,1H),8.49(d,J＝6.4Hz,1H),8.62-8.63(m,1H),9.35(s,1H),11.06(s,1H).(M+H)+ 773.5.
Using a procedure similar to that described above, compounds 125 (also using the procedure described in compound 67), 148 (also using the procedure described in compound 67), and compound 170 were prepared.
Synthetic scheme for exemplary Compound 106
Prepared according to the following synthetic schemes using the procedures described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 106：1H NMR(400MHz,DMSO-d6):δ1.54-1.68(m,10H),1.84-1.88(m,2H),2.12-2.14(m,1H),2.77-2.93(m,5H),3.40-3.45(m,4H),3.64-3.75(m,4H),3.91(s,3H),4.09(t,J＝6.4Hz,2H),4.39-4.46(m,1H),4.89-4.99(m,1H),5.41-5.50(m,1H),6.90(d,J＝8.4Hz,1H),7.14-7.2(m,1H),7.32-7.35(m,2H),7.48(d,J＝8.0Hz,1H),7.55(s,1H),7.76(d,J＝8.0Hz,1H),7.92-8.00(m,1H),8.21(d,J＝8.0Hz,1H),8.43(d,J＝2.0Hz,1H),8.59(d,J＝5.6Hz,1H),9.33(s,1H).(M+H)+ 759.6.
Synthetic scheme for exemplary Compound 107
2- (2, 6-Dioxopiperidin-3-yl) -5- (4- (4- (6- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -2-aza-spiro [3.3] heptane-2-yl) butoxy) isoindoline-1, 3-dione
Prepared according to the following synthetic schemes using the procedures described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 107：1HNMR(400MHz,CDCl3):δ1.61-1.65(m,2H),1.72-1.77(m,4H),1.90-1.93(m,2H),1.99-2.04(m,1H),2.14-2.22(m,3H),2.44-2.49(m,2H),2.78-3.01(m,6H),3.44-3.49(m,4H),3.92(s,3H),3.99-4.05(m,2H),4.14(t,J＝6.2Hz,2H),4.94-4.98(m,1H),5.17-5.20(m,1H),6.81(d,J＝8.4Hz,1H),7.19-7.21(m,1H),7.33-7.37(m,2H),7.49(d,J＝8.4Hz,1H),7.56(s,1H),7.78(d,J＝8.4Hz,1H),7.90-7.93(m,1H),8.21(d,J＝8.4Hz,1H),8.35(br,1H),8.45-8.46(m,1H),8.59(d,J＝5.6Hz,1H),9.34(s,1H).(M+H)+771.6.
Synthetic schemes for exemplary Compound 108
2- (2, 6-Dioxopiperidin-3-yl) -5- ((6- ((6- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) oxy) hexyl) oxy) isoindoline-1, 3-dione
Prepared according to the following synthetic schemes using the procedures described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 108：1H NMR(400MHz,DMSOd-6):δ1.43-1.44(m,4H),1.70-1.74(m,4H),1.98-2.04(m,1H),2.44-2.47(m,1H),2.56-2.60(m,1H),2.65(t,J＝6.0Hz,4H),2.83-2.92(m,1H),3.95(s,3H),4.10(t,J＝6.0Hz,2H),4.22(t,J＝6.4Hz,2H),5.07-5.11(m,1H),5.30-5.35(m,1H),5.39-5.45(m,1H),6.34-6.37(m,2H),6.98(d,J＝8.4Hz,1H),7.24-7.26(m,1H),7.33(d,J＝2.0Hz,1H),7.59-7.65(m,3H),7.72(d,J＝8.0Hz,1H),7.97(s,1H),8.17-8.21(m,1H),8.31(d,J＝8.0Hz,1H),8.50(d,J＝6.0Hz,1H),8.65(d,J＝2.0Hz,1H),9.36(s,1H),11.10(s,1H).(M+H)+ 795.5.
Synthetic scheme for exemplary Compound 109
2- (2, 6-Dioxopiperidin-3-yl) -5- ((6- ((4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) oxy) hexyl) oxy) isoindoline-1, 3-dione
Prepared according to the following synthetic schemes using the procedures described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 109：1H NMR(400MHz,DMSOd-6):δ1.47(s,4H),1.72-1.78(m,4H),2.02-2.05(m,2H),2.33(s,1H),2.63-2.66(m,4H),2.88-2.89(m,1H),3.41-3.49(m,2H),3.96(s,2H),4.18-4.23(m,3H),5.04-5.12(m,2H),5.42(br,1H),6.19(s,1H),6.55-6.56(m,1H),6.98(d,J＝8.4Hz,1H),7.34(d,J＝7.2Hz,1H),7.41(s,1H),6.63(s,2H),7.81-7.83(m,1H),7.95-7.97(m,2H),8.21(d,J＝8.4Hz,1H),8.32(d,J＝7.2Hz,1H),8.50(d,J＝4.0Hz,1H),8.64(s,1H),9.36(s,1H),11.11(s,1H).(M+H)+ 795.5.
Synthetic scheme for exemplary Compound 111
2- (2, 6-Dioxopiperidin-3-yl) -5- (3- ((3- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) prop-2-yn-1-yl) oxy) azetidin-1-yl) isoindoline-1, 3-dione
Step 1 tert-butyl 3- (prop-2-yn-1-yloxy) azetidine-1-carboxylic acid ester
To a stirred solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (1.0 g,12.2 mmol) in N, N-dimethylformamide (10 ml) at 0℃was added sodium hydride (60% in mineral oil) (255 mg,6.36 mmol) and the resulting mixture was stirred at 0℃for 30min. The reaction mixture was allowed to warm to room temperature and stirred for an additional 30 minutes, then 3-bromoprop-1-yne (818 mg,6.94 mmol) was added, and the resulting reaction mixture was stirred at 50 ℃ overnight. LCMS showed the reaction was complete. The reaction mixture was quenched with water (10 ml) at 0 ℃ and extracted with ethyl acetate (30 ml x 2). The combined organic layers were washed with brine (30 ml x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (eluting with 10% ethyl acetate in hexane) to give tert-butyl 3- (prop-2-yn-1-yloxy) azetidine-1-carboxylate (1.03 g, yield 84%) as a colourless oil.
Step 2 tert-butyl 3- ((3- (5-hydroxypyridin-2-yl) prop-2-yn-1-yl) oxy) azetidine-1-carboxylate
To a stirred solution of tert-butyl 3- (prop-2-yn-1-yloxy) azetidine-1-carboxylate (900 mg,4.27 mmol) and 6-bromopyridin-3-ol (284 mg,4.27 mmol) in acetonitrile (10 ml) under nitrogen atmosphere at room temperature was added triethylamine (863 mg,8.54 mmol) followed by bis (triphenylphosphine) palladium (II) chloride (150 mg,0.214 mmol) and cuprous iodide (41 mg,0.214 mmol), and the mixture was degassed three times with nitrogen. The reaction mixture was allowed to warm to 65 ℃ and stirred overnight. TLC showed the reaction was complete. The mixture was partitioned between ethyl acetate (100 ml) and water (50 ml). The organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash column chromatography (eluting with 100% ethyl acetate in hexane) to give tert-butyl 3- ((3- (5-hydroxypyridin-2-yl) prop-2-yn-1-yl) oxy) azetidine-1-carboxylate (550 mg, 42% yield) as a brown oil.
Step 3 tert-butyl 3- (3- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) prop-2-yn-1-yl) oxy) azetidine-1-carboxylate
A solution of tert-butyl 3- ((3- (5-hydroxypyridin-2-yl) prop-2-yn-1-yl) oxy) azetidine-1-carboxylate (100 mg,0.325 mmol), (1 s,3 s) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutyl methane sulfonate (137 mg,0.325 mmol) and cesium carbonate (211 mg,0.65 mmol) in anhydrous N, N-dimethylformamide (2 ml) was stirred at 70℃for 36H. TLC showed the reaction was complete. The mixture was partitioned between ethyl acetate (50 ml) and water (25 ml). The organic layer was collected, washed with brine (25 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by flash column chromatography on silica gel (eluting with 3% methanol in dichloromethane) to give tert-butyl 3- ((3- (5- ((1 r,3 r) -3- ((5- (5- (methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) prop-2-yn-1-yl) oxy) azetidine-1-carboxylate (60 mg, 29%) as a white solid.
According to the following synthetic schemes, tert-butyl 3- ((3- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin-2-yl) cyclobutoxy) pyridin-2-yn-1-yl) oxy) azetidine-1-carboxylate is converted to the final compound, 2- (2, 6-dioxopiperidin-3-yl) -5- (3- ((3- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin-2-yl) cyclobutoxy) pyridin-2-yl) prop-2-yn-1-yl) oxy) azetidine-1-yl) isoindoline-1, 3-dione, using the procedure described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 111：1HNMR(400MHz,DMSO-d6):δ1.98-2.02(m,1H),2.54-2.73(m,6H),2.83-2.92(m,1H),3.95-3.97(m,5H),4.31-4.34(m,2H),4.50(s,2H),4.67-4.72(m,1H),5.04-5.13(m,2H),5.42-5.48(m,1H),6.67-6.69(m,1H),6.82(s,1H),6.69-7.01(m,1H),7.33-7.36(m,1H),7.53-7.55(m,1H),7.63-7.67(m,3H),8.01(s,1H),8.21-8.26(m,2H),8.33-8.37(m,1H),8.51-8.55(m,1H),8.65-8.66(m,1H),9.39(s,1H),11.07(s,1H).(M+H)+788.5.
The following exemplary compound 194 was prepared using a similar procedure.
Synthetic schemes for exemplary Compound 114
2- (2, 6-Dioxopiperidin-3-yl) -5- ((5- (4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) butoxy) pentyl) oxy) isoindoline-1, 3-dione
Prepared according to the following synthetic schemes using the procedures described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 114：1H NMR(400MHz,CDCl3):δ1.52-1.59(m,2H),1.63-1.67(m,5H),1.83-1.90(m,1H),2.11-2.16(m,2H),2.43-2.54(m,4H),2.71-2.92(m,4H),3.39-3.49(m,6H),3.95(s,3H),4.08(t,J＝6.4Hz,2H),4.23-4.29(m,1H),4.94(dd,J＝5.2,12.0Hz,1H),6.83(d,J＝8.4Hz,1H),7.17(dd,J＝2.0,8.0Hz,1H),7.32(d,J＝1.6Hz,1H),7.44(d,J＝6.0Hz,1H),7.54(d,J＝8.0Hz,1H),7.60(s,1H),7.75(d,J＝8.4Hz,1H),7.91(dd,J＝2.4,8.8Hz,1H),8.14(m,1H),8.21(d,J＝8.0Hz,1H),8.48(d,J＝2.4Hz,1H),8.58(d,J＝5.2Hz,1H),9.34(s,1H).(M+H)+ 760.5.
Compound 115 was prepared using a procedure similar to that of compound 140.
Synthetic scheme for exemplary Compound 116
2- (2, 6-Dioxopiperidin-3-yl) -5- ((2- (4- (4- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) butoxy) butyl) -2-azaspiro [3.3] heptan-6-yl) oxy) isoindoline-1, 3-dione
Prepared according to the following synthetic schemes using the procedures described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 116：1HNMR(400MHz,CDCl3):δ1.39-1.42(m,2H),1.47-1.52(m,2H),1.64-1.70(m,2H),1.77-1.82(m,2H),2.01-2.07(m,1H),2.21-2.26(m,2H),2.54-2.64(m,3H),2.75-2.90(m,5H),3.42-3.45(m,3H),3.61-3.71(m,4H),3.95(s,3H),4.35(t,J＝6.2Hz,2H),4.78-4.82(m,1H),5.09-5.13(m,1H),6.94(d,J＝8.4Hz,1H),7.20-7.25(m,2H),7.60-7.63(m,2H),7.79(d,J＝8.0Hz,1H),7.97(s,1H),8.18-8.20(m,1H),8.31(d,J＝8.0Hz,1H),8.48(d,J＝5.2Hz,1H),8.65(s,1H),9.34(s,1H),11.11(s,1H).(M+H)+ 771.6.
Synthesis scheme for Compound 118
2- (2, 6-Dioxopiperidin-3-yl) -5- (3- ((3- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) -3- (trifluoromethyl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yn-1-yl) oxy) azetidin-1-yl) isoindoline-1, 3-dione
Prepared according to the following synthetic schemes using the procedures described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 118：1H NMR(400MHz,DMSO-d6):δ1.98-2.03(m,1H),2.09-2.15(m,1H),2.20-2.24(m,1H),2.70-2.87(m,5H),4.01-4.04(m,4H),4.29-4.34(m,1H),4.46(s,2H),4.75-4.79(m,1H),4.89-4.95(m,1H),5.00-5.06(m,1H),5.33-5.40(m,2H),5.65-5.70(m,1H),6.53-6.55(m,1H),6.79(s,1H),7.08-7.11(m,1H),7.40(d,J＝8.0Hz,1H),7.56-7.65(m,4H),7.95(s,1H),8.19-8.30(m,3H),8.60-8.64(m,2H),9.38(s,1H).(M+H)+ 856.5.
Synthetic scheme for exemplary Compound 121
(2S, 4R) -1- ((S) -20- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -2- (tert-butyl) -4-oxo-6,9,12,15,18-pentoxy-3-azaeicosyl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide
Step 1:14- ((5-bromopyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecan-1-ol
To a solution of 3,6,9, 12-tetraoxatetradecane-1, 14-diol (20 g,83.93 mmol) in N, N-dimethylformamide (100 ml) at 0℃was added sodium hydride (60% in mineral oil) (1.36 g,34.09 mmol), and the resulting mixture was stirred at 0℃for 30 minutes. Then 5-bromo-2-fluoropyridine (5 g,28.41 mmol) was added and the resulting reaction mixture was stirred at 50 ℃ for 2 hours. TLC showed the reaction was complete. The reaction mixture was quenched with water (150 ml) at 0 ℃ and extracted with ethyl acetate (150 ml x 2). The combined organic layers were washed with brine (200 ml x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluting with 2% methanol in dichloromethane) to give 14- ((5-bromopyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecan-1-ol as a colourless oil (8 g, 72% yield).
Step 2 t-butyl 17- ((5-bromopyridin-2-yl) oxy) -3,6,9,12, 15-pentaoxaheptadecane-1-oic acid ester
To a stirred solution of 14- ((5-bromopyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecan-1-ol (2.00 g,5.07 mmol) and tetrabutylammonium chloride (1.41 g,5.07 mmol) in dichloromethane (20 ml) and sodium hydroxide (20 ml,35% aqueous solution) at 0℃was added tert-butyl 2-bromoacetate (2.97 g,15.22 mmol). The reaction mixture was then allowed to warm to room temperature and stirred at room temperature overnight. The organic layer was collected and the aqueous layer was extracted with dichloromethane (20 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash column chromatography (eluting with 50% ethyl acetate in hexane) to give tert-butyl 17- ((5-bromopyridin-2-yl) oxy) -3,6,9,12, 15-pentaoxaheptadecane-1-carboxylate (1.64 g, yield 64%) as a colorless oil.
Step 3 tert-butyl 17- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3,6,9,12, 15-pentaoxaheptadecane-1-oic acid ester
To 7-bromo-5H-pyrido [4,3-b ] indole (300 mg,1.22 mmol), 4', 5',5' -octamethyl-2, 2' -bis (1, 3, 2-dioxaborane) (620 mg,2.44 mmol) and potassium acetate (239 mg,2.44 mmol) in a stirred solution of dioxane (5 ml), 1,1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (176 mg,0.24 mmol) was added and the mixture was degassed three times with nitrogen. The resulting mixture was stirred at 90 ℃ overnight. LCMS showed the reaction was complete. 14- ((5-bromopyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecan-1-ol (93mg, 1.83 mmol), aqueous sodium carbonate (2N, 3.2 ml) and tetrakis (triphenylphosphine) palladium (70 mg,0.06 mmol) were added to the reaction mixture, and the mixture was degassed three times with nitrogen. The resulting mixture was stirred under nitrogen atmosphere at 80 ℃ for 3 hours. The reaction mixture was partitioned between ethyl acetate (30 ml) and water (20 ml). The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (20 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluting with 2% methanol in dichloromethane) to give tert-butyl 17- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3,6,9,12, 15-pentaoxaheptadecane-1-ate as a grey oil (260 mg, 36% yield).
Step 4:17- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3,6,9,12, 15-pentaoxaheptadecane-1-acid
A mixture of tert-butyl 17- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3,6,9,12, 15-pentaoxaheptadecane-1-carboxylate (130 mg,0.22 mmol) and 2, 2-trifluoroacetic acid (2 ml) in dichloromethane (1 ml) was stirred at room temperature for one hour. The volatiles were evaporated under reduced pressure to give 17- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3,6,9,12, 15-pentaoxaheptadecane-1-acid (120 mg, crude) as a brown solid, which was used in the next step without further purification.
Step 5 (2S, 4R) -1- ((S) -20- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -2- (tert-butyl) -4-oxo-6,9,12,15,18-pent-3-azol-1-yl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide
To a stirred solution of 17- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3,6,9,12, 15-pentaoxaheptadecane-1-acid (120 mg, crude), (2S, 4 r) -1- ((S) -2-amino-3, 3-dimethylbutyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide hydrochloride (105 mg,0.22 mmol) and N-ethyl-N-isopropyl-2-amine (142 mg,1.10 mmol) in anhydrous N, N-dimethylformamide (3 ml) was added HATU (2- (7-aza-1H-benzotriazol-1-yl) -1, 3-tetramethyluronium hexafluorophosphate) (167mg, 0.44 mmol) and stirred for 20 minutes at room temperature. The mixture was partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer was collected, washed with brine (20 ml x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by preparative TLC (eluting with 10% methanol in dichloromethane) to give (2S, 4 r) -1- ((S) -20- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -2- (tert-butyl) -4-oxo-6,9,12,15,18-pentaoxa-3-aza-twenty-1-acyl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide as a white solid (28 mg, 13% yield).
1H NMR(400MHz,DMSOd-6):δ0.93(s,9H),1.36-1.47(m,3H),1.73-1.80(m,1H),1.96-2.09(m,2H),3.23-3.60(m,16H),3.79(t,J＝3.6Hz,2H),3.96(s,2H),4.28(s,1H),4.42-4.46(m,3H),4.54(d,J＝9.6Hz,1H),4.90(t,J＝7.6Hz,1H),5.12(s,1H),6.97(d,J＝8.4Hz,1H),7.35-7.43(m,5H),7.65-7.69(m,2H),7.87(s,1H),8.12-8.15(m,1H),8.37-8.43(m,2H),8.51(d,J＝5.6Hz,1H),8.59(d,J＝1.6Hz,1H),8.97(s,1H),9.51(s,1H),12.28(s,1H).(M+H)+ 966.7.
Similar procedures were used to prepare compound 1, compound 5, compound 6, compound 120 and compound 122.
Synthetic schemes for exemplary Compound 119
(2S, 4R) -1- ((S) -17- ((5- (5H-pyrido [4,3-b ] indol-7-yl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -2- (tert-butyl) -4-oxo-6, 9,12, 15-tetraoxa-3-aza-heptadecanoyl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide
Prepared according to the following synthetic schemes using the procedures described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 119：1H NMR(400MHz,DMSO-d6):δ0.93(s,9H),1.35(t,J＝6.8Hz,3H),1.77-1.78(s,1H),2.02-2.04(m,1H),2.44(s,3H),3.53-3.64(m,14H),3.80-3.85(m,2H),3.95(s,2H),4.28(s,1H),4.44(d,J＝8.2Hz,1H),4.54(d,J＝9.6Hz,1H),4.58-4.63(m,2H),4.90(s,1H),5.12(s,1H),7.26-7.50(m,5H),7.54(d,J＝5.8Hz,1H),7.66(d,J＝8.2Hz,1H),7.90(s,1H),8.35(d,J＝8.0Hz,1H),8.42-8.45(m,3H),8.85(s,1H),8.97(s,1H),9.41(s,1H),11.92(s,1H).(M+H)+ 990.7.
Synthetic scheme for exemplary Compound 126
2- (2, 6-Dioxopiperidin-3-yl) -5- ((5- (6- (methyl ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutyl) amino) -2-azaspiro [3.3] heptan-2-yl) pentyl) oxy) isoindoline-1, 3-dione
Step 1 (1 r,3 r) -3- (methylamino) cyclobutanol
To a solution of tert-butyl ((1 r,3 r) -3-hydroxycyclobutyl) carbamate (2 g,10.7 mmol) in tetrahydrofuran (30 ml) at 0℃was added lithium aluminum hydride (1.6 g,42.7 mmol). The mixture was stirred at 65 ℃ for 2 hours. TLC showed the reaction was complete. The mixture was quenched with water (1.6 ml), sodium hydroxide (1.6 ml, 15% in water) and water (4.8 ml) at 0 ℃. The mixture was stirred at room temperature for 15 min and filtered. The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude (1 r,3 r) -3- (methylamino) cyclobutanol (1.3 g) as a colorless oil, which was used in the next step without further purification.
Step 2 t-butyl ((1 r,3 r) -3-hydroxycyclobutyl) (methyl) carbamate
To a solution of (1 r,3 r) -3- (methylamino) cyclobutanol (1.3 g,12.8 mmol) and triethylamine (2.6 g,25.7 mmol) in dichloromethane (10 ml) at room temperature was added di-tert-butyl carbonate (4.2 g, 19.28 mmol). The mixture was stirred at room temperature for 12 hours. TLC showed the reaction was complete. The mixture was diluted with dichloromethane (10 ml) and washed with aqueous hydrochloric acid (1 n,10 ml). The organic layer was collected, washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluting with 33-50% ethyl acetate in hexane) to give tert-butyl ((1 r,3 r) -3-hydroxycyclobutyl) (methyl) carbamate (1.2 g, two steps 56%) as a colorless oil.
Step 3 tert-Butylmethyl ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutyl) carbamate
To a solution of 7- (6-fluoropyridin-3-yl) -5-methyl-5H-pyrido [4,3-b ] indole (300 mg,1.1 mmol) and tert-butyl ((1 r,3 r) -3-hydroxycyclobutyl) (methyl) carbamate (218 mg,1.1 mmol) in 1-methylpyrrolidin-2-one (3 ml) at 0℃was added sodium hydride (60% in mineral oil). The mixture was cooled to room temperature and stirred at room temperature for 30 minutes. LC-MS showed the reaction was complete. The mixture was partitioned between ethyl acetate (30 ml) and water (30 ml). The organic layer was collected, washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluting with 1-2% methanol in dichloromethane) to give tert-butylmethyl ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutyl) carbamate (450 mg, 91%) as a pale yellow oil.
Step 4. Tert-butyl 6- (methyl ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutyl) amino) -2-azaspiro [3.3] heptane-2-carboxylic acid ester
A mixture of tert-butylmethyl ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutyl) carbamate (450 mg,0.98 mmol) and 2, 2-trifluoroacetic acid (2 ml) in dichloromethane (2 ml) was stirred at room temperature for 1 hour. TLC showed the reaction was complete. The volatiles were evaporated under reduced pressure. At 0 ℃, the residue was taken up in methanol (5 ml) followed by sequential addition of N-ethyl-N-isopropyl-2-amine (380 mg,2.94 mmol), tert-butyl 6-oxo-2-azaspiro [3.3] heptane-2-carboxylate (207 mg,0.98 mmol) and acetic acid (71 mg,1.18 mmol). The resulting mixture was stirred at room temperature for 30 minutes, and sodium cyanoborohydride (124 mg,1.96 mmol) was added. The mixture was stirred at room temperature for 18 hours. TLC showed the reaction was complete. The mixture was concentrated, and the residue was partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer was collected, washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluting with 2-5% methanol in dichloromethane) to give tert-butyl 6- (methyl ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutyl) amino) -2-azaspiro [3.3] heptane-2-carboxylate (240 mg, two steps 44%) as a white solid.
Step 5N-methyl-N- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-one) oxy) cyclobutyl) -2-azaspiro [3.3] heptane-6-amine
A mixture of tert-butyl 6- (methyl ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutyl) amino) -2-azaspiro [3.3] heptane-2-carboxylate (100 mg,0.18 mmol) and 2, 2-trifluoroacetic acid (0.5 ml) in anhydrous dichloromethane (0.5 ml) was stirred at room temperature for 1 hour. TLC showed the reaction was complete. The mixture was concentrated under reduced pressure to give crude N-methyl-N- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutyl) -2-azaspiro [3.3] heptane-6-amine (100 mg), which was used in the next step without further purification.
Step 6 2- (2, 6-Dioxopiperidin-3-yl) -5- ((5- (6- (methyl ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutyl) amino) -2-azaspiro [3.3] heptan-2-yl) pentyl) oxy) isoindoline-1, 3-dione
N-methyl-N- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutyl) -2-azaspiro [3.3] heptan-6-amine (100 mg, crude) and N-ethyl-N-isopropyl-2-amine (70 mg,0.54 mmol) in methanol (10 ml) were added to 5- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) valeraldehyde (65 mg,0.18 mmol) and acetic acid (13 mg,0.21 mmol) at 0 ℃. The mixture was stirred at room temperature for 30 minutes, then sodium cyanoborohydride (23 mg,0.36 mmol) was added. The mixture was stirred at room temperature for 16 hours. TLC showed the reaction was complete. The mixture was concentrated under reduced pressure to give a crude residue which was purified by HPLC to give 2- (2, 6-dioxopiperidin-3-yl) -5- ((5- (6- (methyl ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutyl) amino) -2-azaspiro [3.3] heptan-2-yl) pentyl) oxy) isoindoline-1, 3-dione (57.3 mg, two steps 40%) as a white solid.
1H NMR(400MHz,DMSO-d6):δ1.42-1.51(m,4H),1.75-1.79(m,2H),2.03-2.06(m,1H),2.54(s,3H),2.58-2.68(m,5H),2.81-2.94(m,2H),3.11-3.17(m,2H),3.61-3.71(m,3H),3.98-4.11(m,6H),4.15(s,3H),4.17-4.23(m,3H),5.10-5.14(m,1H),5.25-5.31(m,1H),7.03(d,J＝8.4Hz,1H),7.33-7.42(m,2H),7.84-7.89(m,1H),8.22-8.32(m,3H),8.55(d,J＝8.0Hz,1H),8.71(s,1H),8.78(d,J＝6.4Hz,1H),9.78(s,1H),10.05(brs,1H),10.51(brs,1H),11.11(s,1H).(M+H)+ 796.6.
Synthetic scheme for exemplary Compound 127
3- (5- (4- ((1- (5- (5-Methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) piperidin-4-yl) methyl) piperazin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione
Step 1 (1- (5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) piperidin-4-yl) methanol
To a mixture of 7- (6-fluoropyridin-3-yl) -5-methyl-5H-pyrido [4,3-b ] indole (200 mg,0.72 mmol) and piperidin-4-ylmethanol (108 mg,0.93 mmol) in 1-methylpyrrolidin-2-one (5 ml) was added potassium carbonate (298 mg,2.16 mmol) and it was stirred under nitrogen atmosphere at 100℃overnight. The cooled reaction mixture was partitioned between ethyl acetate (30 ml) and water (30 ml). The organic layer was collected, washed with brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluting with 2-5% methanol in dichloromethane) to give (1- (5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) piperidin-4-yl) methanol (205 mg, 76% yield) as a pale yellow solid.
Step 21- (5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) piperidine-4-carbaldehyde
To a solution of dess-martin periodate (136 mg,0.32 mmol) in dichloromethane (3 ml) was added (1- (5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) piperidin-4-yl) methanol (60 mg,0.16 mmol) and stirred at room temperature under nitrogen atmosphere for 1 hour. The reaction mixture was partitioned between dichloromethane (20 ml) and water (20 ml). The organic layer was collected, washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by preparative TLC (eluting with 3% methanol in dichloromethane) to give 1- (5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) piperidine-4-carbaldehyde as a white solid (58 mg, 97% yield).
Step 3 tert-butyl 4- (1-oxo-3H-isobenzofuran-5-yl) piperazine-1-carboxylate
To a solution of 5-bromo-3H-isobenzofuran-1-one (45 g,211.24mmol,1.00 eq.) and tert-butylpiperazine-1-carboxylate (39.34 g,211.24mmol,1.00 eq.) in dioxane (500 mL) was added tris (dibenzylideneacetone) dipalladium (0) (19.34 g,21.12mmol,0.10 eq.), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (12.22 g,21.12mmol,0.10 eq.) and potassium phosphate (89.68 g,422.48mmol,2.00 eq.). The mixture was heated to 100 ℃ for 16 hours under nitrogen protection. The mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo. The residue was triturated in ethyl acetate: petroleum ether (500 ml, v/v=1:2). Tert-butyl 4- (1-oxo-3H-isobenzofuran-5-yl) piperazine-1-carboxylate (50 g,122.5mmol,58% yield, 78% purity) was obtained as a yellow solid.
Step 4- (4-tert-Butoxycarbonylpiperazin-1-yl) -2- (hydroxymethyl) benzoic acid
To a mixture of tert-butyl 4- (1-oxo-3H-isobenzofuran-5-yl) piperazine-1-carboxylate (47.8 g,150.14mmol,1.00 eq.) in tetrahydrofuran (150 mL), methanol (150 mL) and water (150 mL) was added sodium hydroxide (24 g,600mmol,4.00 eq.). The mixture was stirred at 25 ℃ for 1 hour. The solution was adjusted to ph=4-5 with aqueous hydrochloric acid (1M) and extracted with ethyl acetate (100 ml x 5). The organic layer was concentrated in vacuo. The crude product was triturated in ethyl acetate: petroleum ether (450 ml, v: v=1:2). 4- (4-t-Butoxycarbonylpiperazin-1-yl) -2- (hydroxymethyl) benzoic acid (40 g,118.91mmol,79% yield) was obtained as a yellow solid.
Step 5 tert-butyl 4- [3- (hydroxymethyl) -4-methoxycarbonyl-phenyl ] piperazine-1-carboxylic acid ester
To a solution of 4- (4-tert-butoxycarbonylpiperazin-1-yl) -2- (hydroxymethyl) benzoic acid (20 g,59.46mmol,1.00 eq.) in methanol (100 mL) and ethyl acetate (100 mL) at-10 ℃ was added TMS-diazomethane (2 m,89mL,3.00 eq.). The solution was stirred at-10 ℃ for 0.25 hours. The solution was quenched with water (300 mL) and extracted with ethyl acetate (150 mL x 3). The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated. Tert-butyl 4- [3- (hydroxymethyl) -4-methoxycarbonyl-phenyl ] piperazine-1-carboxylic acid ester (20.84 g, crude) was obtained as a brown oil.
Step 6 tert-butyl 4- [3- (bromomethyl) -4-methoxycarbonyl-phenyl ] piperazine-1-carboxylic acid ester
To a solution of tert-butyl 4- [3- (hydroxymethyl) -4-methoxycarbonyl-phenyl ] piperazine-1-carboxylate (20.84 g,59.47mmol,1.00 eq.) in tetrahydrofuran (200 mL) was added triphenylphosphine (23.4 g,89.21mmol,1.50 eq.) and tetrabromomethane (29.58 g,89.21mmol,1.50 eq.). The solution was stirred at 25 ℃ for 1 hour. The solution was quenched with water (200 mL) and extracted with ethyl acetate (100 mL x 2). The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate: petroleum ether=1:50-1:8). Tert-butyl 4- [3- (bromomethyl) -4-methoxycarbonyl-phenyl ] piperazine-1-carboxylic acid ester (12 g,29.03mmol,49% yield) was obtained as a pale yellow oil.
Step 7 tert-butyl 4- [2- (2, 6-dioxo-3-piperidyl) -1-oxo-isoindolin-5-yl ] piperazine-1-carboxylic acid ester
To a solution of tert-butyl 4- [3- (bromomethyl) -4-methoxycarbonyl-phenyl ] piperazine-1-carboxylate (12 g,29.03mmol,1.00 eq.) in acetonitrile (300 mL) was added 3-aminopiperidine-2, 6-dione, hydrochloride (7.17 g,43.55mmol,1.50 eq.) and N-ethyl-N-isopropyl-2-amine (11.26 g,87.09mmol,15mL,3.00 eq.). The solution was stirred at 80 ℃ for 16 hours. LCMS showed the reaction was almost complete. The reaction mixture was cooled to 20 ℃ and filtered. The solid was washed with acetonitrile (30 mL). Tert-butyl 4- [2- (2, 6-dioxo-3-piperidinyl) -1-oxo-isoindolin-5-yl ] piperazine-1-carboxylate (6 g,14mmol,48% yield) was obtained as a white solid.
Step 8 3- (1-oxo-5-piperazin-1-yl-isoindolin-2-yl) piperidine-2, 6-dione
To a mixture of tert-butyl 4- [2- (2, 6-dioxo-3-piperidinyl) -1-oxo-isoindolin-5-yl ] piperazine-1-carboxylate (6 g,14mmol,1.00 eq.) in dioxane (70 mL) was added the hydrochloride salt/dioxane (4 m,100mL,28.57 eq.). The mixture was stirred at 25 ℃ for 2 hours. The mixture was poured into ethyl acetate (400 mL) and stirred for 30min. The suspension was filtered and the solids were collected. 3- (1-oxo-5-piperazin-1-yl-isoindolin-2-yl) piperidine-2, 6-dione (5 g,13.71mmol,98% yield, hydrochloride) was obtained as a white solid.
Step 9 3- (5- (4- ((1- (5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) piperidin-4-yl) methyl) piperazin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione
A mixture of 1- (5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) piperidine-4-carbaldehyde (58 mg,0.15 mmol), N-ethyl-N-isopropyl-2-amine (32 mg,0.23 mmol), 3- (1-oxo-5- (piperazin-1-yl) isoindolin-2-yl) piperidine-2, 6-dione (51 mg,0.15 mmol) and acetic acid (0.5 ml) in methanol (4 ml) was stirred at room temperature for 30 minutes. It was followed by the addition of sodium cyanoborohydride (21 mg,2.10 mmol) and stirring at room temperature for 1 hour. The mixture was partitioned between ethyl acetate (30 ml) and brine (30 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified by preparative TLC (eluting with 10% methanol in dichloromethane) to give 3- (5- (4- ((1- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) piperidin-4-yl) methyl) piperazin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (57 mg, 53%) as a pale yellow solid.
1H NMR(400MHz,DMSO-d6):δ1.11-1.23(m,4H),1.82-1.99(m,4H),2.30-2.39(m,3H),2.60(br,4H),2.86-2.94(m,3H),3.17(s,2H),3.98(s,3H),4.10(br,1H),4.21(d,J＝16.8Hz,1H),4.32-4.41(m,3H),5.05(dd,J＝13.2Hz,1H),6.96(d,J＝9.2Hz,1H),706-7.08(m,2H),7.53(d,J＝8.4Hz,1H),7.62(d,J＝8.0Hz,1H),7.69(d,J＝6.0Hz,1H),7.95(s,1H),8.02(dd,J＝9.2Hz,1H),8.30(dd,J＝8.4Hz,1H),8.51(d,J＝5.6Hz,1H),8.64(s,1H),9.38(s,1H),10.95(s,1H).(M+H)+ 683.5.
Synthetic schemes for exemplary Compound 128
3- (5- (4- (2- (1- (5- (5-Methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) piperidin-4-yl) ethyl) piperazin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione
Prepared according to the following synthetic protocol using the procedure described for compound 127.
Compounds of formula (I) 128：1H NMR(400MHz,DMSO-d6)δ1.16-1.23(m,3H),1.40-1.50(m,2H),1.61(br,1H),1.76-1.78(m,2H),1.94-1.96(m,1H),2.38-2.41(s,3H),2.51-2.56(m,4H),2.82-2.90(m,3H),3.29-3.33(m,4H),3.95(s,3H),4.18-4.22(m,1H),4.30-4.39(m,3H),5.02-5.08(m,1H),6.95(d,J＝8.8Hz,1H),7.05-7.06(m,2H),7.50-7.69(m,3H),7.91(s,1H),8.00(dd,J＝8.8,2.2Hz,1H),8.28(d,J＝8.0Hz,1H),8.48(d,J＝5.8Hz,1H),8.62(d,J＝2.0Hz,1H),9.33(s,1H),10.95(s,1H).(M+H)+ 697.6.
Synthetic scheme for exemplary Compound 130
2- (2, 6-Dioxopiperidin-3-yl) -5- (3- (3- (4- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) -3- (trifluoromethyl) pyridin-2-yl) oxy) piperidin-1-yl) propoxy) azetidin-1-yl) isoindoline-1, 3-dione
Prepared according to the following synthetic schemes using the procedures described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 130：1H NMR(400MHz,DMSO-d6):δ1.74-1.80(m,4H),1.85-1.92(m,2H),1.97-2.02(m,2H),2.02-2.15(m,2H),2.54-2.58(m,2H),2.67-2.91(m,4H),3.41-3.50(m,8H),3.81-3.88(m,2H),3.98(s,3H),4.25(t,J＝7.8Hz,2H),4.44-4.49(m,1H),5.05(dd,J＝5.2,12.8Hz,1H),5.33-5.40(m,1H),6.66(dd,J＝1.6,8.4Hz,1H),6.80(d,J＝1.2Hz,1H),7.63-7.72(m,3H),8.10(s,1H),8.36(d,J＝8.4Hz,1H),8.51(d,J＝4.8Hz,2H),8.92(s,1H),9.39(s,1H),11.06(s,1H).(M+H)+ 854.6.
Synthetic schemes for exemplary Compound 129
2- (2, 6-Dioxopiperidin-3-yl) -5- ((1, 1-trifluoro-6- (2- (2- (2- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin-2-yl) oxy) ethoxy) hex-2-yl) oxy) isoindoline-1, 3-dione
Step 16- (2- (2- (2- (5-bromopyridin-2-yloxy) ethoxy) -1, 1-trifluorohex-2-ol
To a solution of 5- (2- (2- (2- (5-bromopyridin-2-yloxy) ethoxy) valeraldehyde (575 mg,1.47 mmol) [ prepared according to the scheme below and using the procedure above and conventional procedures known to those skilled in the art ] and CF 3Si(CH3)3 (320 mg,2.21 mmol) in THF was added TBAF (1M, 2.2mL,2.20 mmol) at room temperature. The reaction was stirred at room temperature for 3 hours. After quenching with 1N HCl (3 mL), the mixture was extracted with EA (30 mL) and washed with brine. The organic phase was dried and concentrated in vacuo. The residue was purified by silica gel (PE: ea=2:1) to give 6- (2- (2- (2- (5-bromopyridin-2-yloxy) ethoxy) -1, 1-trifluorohex-2-ol (400 mg,60% yield).
Step 2 6- (2- (2- (2- (5-bromopyridin-2-yloxy) ethoxy) -1, 1-trifluoro-hex-2-yl triflate
To a solution of 6- (2- (2- (2- (5-bromopyridin-2-yloxy) ethoxy) -1, 1-trifluorohex-2-ol (130 mg, 0.28) and pyridine (67 mg,0.85 mmol) in DCM was added Tf 2O (120 mg,0.42 mmol) at 0deg.C. The resulting solution was warmed to room temperature for a total of 1 hour. The reaction was diluted with DCM (10 mL), washed with water, brine and concentrated in vacuo to give 6- (2- (2- (2- (5-bromopyridin-2-yloxy) ethoxy) -1, 1-trifluorohex-2-yl triflate (160 mg, 96%).
Compounds of formula (I) 129：1HNMR(400MHz,CDCl3):δ9.25(s,1H),8.48(s,1H),8.39(s,1H),8.09(d,J＝8.0Hz,1H),7.82(d,J＝8.0Hz,1H),7.72(d,J＝8.4Hz,1H),7.46(s,1H),7.36-7.41(m,2H),7.19-7.24(m,2H),6.82(d,J＝8.8Hz,1H),4.86-4.91(m,1H),4.58-4.63(m,1H),4.45-4.48(m,2H),3.78-3.82(m,5H),3.55-3.80(m,9H),3.39-3.50(m,3H),2.69-2.82(m,6H),1.96-2.05(m,2H),1.81-1.89(m,2H).(M+H)+ 818.5.
Synthetic schemes for exemplary Compound 131
2- (2, 6-Dioxopiperidin-3-yl) -5- ((17- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3,6,9,12, 15-pentaoxaheptadecyl) oxy) isoindoline-1, 3-dione
Prepared according to the following protocol using the procedure described above and conventional procedures known to those skilled in the art.
Using a procedure similar to compound 131, compound 132 was prepared.
Synthetic scheme for exemplary Compound 133
2- (2, 6-Dioxopiperidin-3-yl) -5- (3- (6- ((5- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) pentyl) oxy) hexyl) azetidin-1-yl) isoindoline-1, 3-dione
Step1 (6- (benzyloxy) hexyl) magnesium bromide
A suspension of (((6-bromohexyl) oxy) methyl) benzene (10 g,0.037 mol), magnesium (1.33 g,0.055 mol) and iodine (200 mg) in anhydrous tetrahydrofuran (100 ml) was stirred at 50℃for 2 hours. Iodine disappeared and the mixture was stirred for an additional 1 hour to give (6- (benzyloxy) hexyl) magnesium bromide (crude), which was used in the next step without further purification.
Step 2 t-butyl 3- (6- (benzyloxy) hexyl) -3-hydroxyazetidine-1-carboxylic acid ester
To a solution of tert-butyl 3-oxoazetidine-1-carboxylate (5.2 g,0.031 mol) in anhydrous tetrahydrofuran (50 ml) at 0℃was added (6- (benzyloxy) hexyl) magnesium bromide. The resulting mixture was allowed to warm to room temperature and stirred at room temperature for 16 hours. The mixture was filtered and the filtrate was concentrated. The residue was partitioned between ethyl acetate (50 ml) and water (100 ml). The organic layer was collected, washed with brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluting with 33-50% ethyl acetate in hexane) to give tert-butyl 3- (6- (benzyloxy) hexyl) -3-hydroxyazetidine-1-carboxylate (1.7 g, two steps 12%) as a colorless oil.
Step3 tert-butyl 3- (6- (benzyloxy) hexylidene) azetidine-1-carboxylic acid ester
To a stirred solution of tert-butyl 3- (6- (benzyloxy) hexyl) -3-hydroxyazetidine-1-carboxylate (800 mg,2.2 mmol) in toluene (10 ml) was added 1-methoxy-N-triethylsulfamoyl-iminoformate (Bogis reagent) (1.57 g,6.6 mmol). The resulting solution was allowed to warm to 90 ℃ and stirred at that temperature for 2 hours. The mixture was poured into water (20 ml) and extracted with ethyl acetate (20 ml x 2). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash column chromatography (eluting with 30% ethyl acetate in hexane) to give tert-butyl 3- (6- (benzyloxy) hexylidene) azetidine-1-carboxylate (125 mg, 16% yield) as a colorless oil.
Step 4 tert-butyl 3- (6-hydroxyhexyl) azetidine-1-carboxylate
A mixture of tert-butyl 3- (6- (benzyloxy) hexamethylene) azetidine-1-carboxylate (125 mg,0.36 mmol), palladium on carbon (10%, 50 mg) in methanol (30 ml) was stirred at room temperature under hydrogen atmosphere (hydrogen balloon) for 3 hours. TLC showed the reaction was complete. Palladium on carbon was removed by filtration and washed with methanol (5 ml x 2). The combined filtrates were concentrated under reduced pressure, to give tert-butyl 3- (6-hydroxyhexyl) azetidine-1-carboxylate (88 mg, yield: 95%) as a colorless oil.
Tert-butyl 3- (6-hydroxyhexyl) azetidine-1-carboxylate was converted to the final compound, 2- (2, 6-dioxopiperidin-3-yl) -5- (3- (6- ((5- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) pentyl) oxy) hexyl) azetidin-1, 3-dione according to the scheme below, and using the procedure described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 133：1H NMR(400Hz,D6-DMSO):δ1.24-1.35(m,7H),1.46-1.57(m,8H),1.72-1.82(m,2H),1.98-2.01(m,3H),2.57-2.74(m,3H),2.81-2.99(m,2H),3.57-3.59(m,2H),3.98(s,3H),4.06-4.08(m,2H),4.33(s,2H),5.03-5.06(m,1H),6.54-6.66(m,1H),6.69(s,1H),6.93-6.95(m,1H),7.57-7.71(m,3H),8.02(s,1H),8.19-8.21(m,1H),8.34-8.36(m,1H),8.53-8.58(m,1H),8.66(s,1H),9.41(s,1H),11.08(s,1H).(M+H)+ 757.6.
Synthetic schemes for exemplary Compound 134
2- (2, 6-Dioxopiperidin-3-yl) -5- ((6- (6- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridazin-3-yl) hex-5-yn-1-yl) oxy) isoindoline-1, 3-dione
Step 1:3, 6-diiodopyrazine
A mixture of 3, 6-dichloropyridazine (5.0 g,34.0 mmol) and sodium iodide (50 g,0.68 mol) in acetone (50 ml) was stirred at 65℃for 3 hours. The reaction mixture was quenched with water (100 ml) and extracted with ethyl acetate (200 ml x 2). The combined organic layers were washed with brine (200 ml x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue which was purified by silica gel flash column chromatography (eluting with 40% ethyl acetate in hexane) to give 3, 6-diiodopyridazine (5.4 g,4.9mol,48% yield) as a brown solid.
Step 2 3-fluoro-6-iodopyrazine
A mixture of 3, 6-dichloropyridazine (1 g,3.0 mmol), cesium fluoride (413 mg,0.9 mol) in dimethyl sulfoxide (10 ml) was stirred overnight at 140 ℃. The reaction mixture was partitioned between water (50 ml) and ethyl acetate (100 ml). The organic layer was collected, washed with brine (100 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by silica gel flash column chromatography (eluting with 20% ethyl acetate in hexane) to give 3-fluoro-6-iodopyridazine (840 mg).
Step 3 7- (6- ((1 r,3 r) -3- ((6-iodopyridazin-3-yl) oxy) cyclobutoxy) pyridin-3-yl) -5-methyl-5H-pyrido [4,3-b ] indole
A solution of (1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutanol (100 mg,0.29 mmol), 3-fluoro-6-iodopyridazine (300 mg,0.10 mmol) in 1-methylpyrrolidin-2-one (5 ml) was added to sodium hydride (60% in mineral oil) (110 mg,2.7 mmol) at 0 ℃. The resulting mixture was allowed to warm to room temperature for a total of 1 hour. The reaction mixture was quenched with water (10 ml) at 0 ℃ and extracted with ethyl acetate (20 ml x 3). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluting with 20% methanol in dichloromethane) to give 7- (6- ((1 r,3 r) -3- ((6-iodopyridazin-3-yl) oxy) cyclobutoxy) pyridin-3-yl) -5-methyl-5H-pyrido [4,3-b ] indole (70 mg,0.13mmol, 44%) as a brown solid.
7- (6- ((1 R,3 r) -3- ((6-iodopyridazin-3-yl) oxy) cyclobutoxy) pyridin-3-yl) -5-methyl-5H-pyrido [4,3-b ] indole was converted to the final compound, 2- (2, 6-dioxopiperidin-3-yl) -5- ((6- (6- ((1 r,3 r) -3- ((5- (5-methyl) -5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridazin-3-yl) hex-5-yn-1-yl) oxy) o-isoindoline-1, 3-dione, according to the following protocol, and using procedure described above (step 6 of compound 73 and step 1 of compound 180).
Compounds of formula (I) 134：1HNMR(400MHz,DMSO-d6):δ1.74-1.78(m,2H),1.92-1.95(m,2H),2.03-2.07(m,1H),2.54-2.62(m,4H),2.68-2.71(m,4H),2.85-2.93(m,1H),3.96(s,3H),4.23-4.27(m,2H),5.09-5.14(m,1H),5.45-5.48(m,1H),5.55-5.58(m,1H),7.01(d,J＝8.8Hz,1H),7.24-7.26(m,1H),7.36-7.38(m,1H),7.45(m,1H),7.62-7.68(m,3H),7.82(d,J＝8.0Hz,1H),7.99(s,1H),8.21-8.24(m,1H),8.33(d,J＝8.0Hz,1H),8.49-8.51(m,1H),8.64-8.65(m,1H),9.37(s,1H),11.12(s,1H).(M+H)+ 776.5.
In addition, compound 149 was prepared from compound 134 using the hydrogenation procedure previously described for the conversion of compound 102 to compound 110.
Synthetic schemes for exemplary Compound 145
2- (2, 6-Dioxopiperidin-3-yl) -5- (4- ((2- (((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutyl) methyl) -2-azaspiro [3.3] heptan-6-yl) oxy) butoxy) isoindoline-1, 3-dione
Prepared according to the schemes below and using the procedures described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 135：1H NMR(400MHz,DMSO-d6):1.60-1.80(m,6H),1.92-2.07(m,5H),2.16-2.26(m,3H),2.34-2.40(m,2H),2.55-2.67(m,4H),2.84-2.93(m,1H),3.26-3.31(m,4H),3.78-3.82(m,1H),3.96(s,3H),4.18(t,J＝6.0Hz,2H),5.05-5.27(m,2H),6.90-6.94(m,1H),7.33-7.35(m,1H),7.42(s,1H),7.60-7.63(m,2H),7.83(d,J＝8.4Hz,1H),7.98(s,1H),8.17-8.20(m,1H),8.32(d,J＝8.0Hz,1H),8.51(d,J＝6.0Hz,1H),8.62(s,1H),9.36(s,1H),11.12(s,1H).(M+H)+ 783.6.
Synthetic scheme for exemplary Compound 136
2- (2, 6-Dioxopiperidin-3-yl) -5- (4- ((2- ((1 s,3 s) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutane-1-carbonyl) -2-azaspiro [3.3] heptan-6-yl) oxy) butoxy) isoindoline-1, 3-dione
Prepared according to the schemes below and using the procedures described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 136：1HNMR(400MHz,DMSO-d6):δ1.61-1.65(m,2H),1.77-1.80(m,2H),1.99-2.08(m,4H),2.14-2.20(m,2H),2.44-2.46(m,3H),2.55-2.61(m,4H),2.72-2.76(m,1H),2.85-2.93(m,1H),3.79-3.84(m,3H),3.96(s,3H),4.04-4.09(m,2H),4.17-4.20(m,2H),5.10-5.14(m,2H),6.93(d,J＝8.4Hz,1H),7.34-7.42(m,2H),7.61-7.65(m,2H),7.83(d,J＝8.0Hz,1H),7.99(s,1H),8.18-8.20(m,1H),8.32(d,J＝8.4Hz,1H),8.50(d,J＝6.0Hz,1H),8.62(d,J＝0.8Hz,1H),9.37(s,1H),11.12(s,1H).(M+H)+ 797.5.
Synthetic scheme for exemplary Compound 137
2- (2, 6-Dioxopiperidin-3-yl) -5- ((5- (6- (methyl ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutyl) amino) -2-azaspiro [3.3] heptan-2-yl) -5-oxopentyl) oxy) isoindoline-1, 3-dione
Step 1 benzyl 5-hydroxy valerate
A mixture of tetrahydro-2H-pyran-2-one (1 g,10 mmol) and sodium hydroxide (400 mg,10 mmol) in water (15 ml) was stirred at 70℃for 16 hours. The mixture was concentrated under reduced pressure to give a crude residue which was dissolved in acetone (20 ml) followed by sequential addition of tetrabutylammonium bromide (161 mg,0.5 mmol) and benzyl bromide (2 g,12 mmol) at room temperature. The mixture was stirred at 60 ℃ for 4 hours. TLC showed the reaction was complete. The mixture was concentrated, and the residue was partitioned between ethyl acetate (30 ml) and water (50 ml). The organic layer was collected, washed with brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluting with 33-50% ethyl acetate in hexane) to give benzyl 5-hydroxyvalerate (500 mg, 24%) as a pale yellow solid.
Benzyl 5-hydroxypentanoate is converted to the final compound, 2- (2, 6-dioxopiperidin-3-yl) -5- ((5- (6- (methyl ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutyl) amino) -2-azaspiro [3.3] heptan-2-yl) -5-oxopentyl) oxy) isoindoline-1, 3-dione according to the scheme below and using the procedure described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 137：1H NMR(400MHz,DMSO-d6):δ1.58-1.63(m,2H),1.72-1.77(m,2H),2.03-2.11(m,3H),2.33-2.47(m,8H),2.54-2.62(m,2H),2.78-2.90(m,3H),3.41-3.48(m,3H),3.75-3.79(m,1H),3.80-3.87(m,1H),4.02(s,3H),4.06(s,1H),4.13-4.18(m,3H),5.10-5.14(m,1H),5.25-5.28(m,1H),6.96-7.00(m,1H),7.33-7.42(m,2H),7.70(d,J＝8.4Hz,1H),7.80-7.84(m,2H),8.06(s,1H),8.23-8.26(m,1H),8.39(d,J＝8.0Hz,1H),8.57-8.67(m,2H),9.49(s,1H),11.12(s,1H).(M+H)+ 810.6.
Synthetic schemes for exemplary Compound 138
5- ((14- ((5- (5- (Difluoromethyl) -5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxymethyl) -3,6,9, 12-tetraoxatetradecyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
Step 15- (difluoromethyl) -7- (6-fluoropyridin-3-yl) -5H-pyrido [4,3-b ] indole
To a solution of 7- (6-fluoropyridin-3-yl) -5H-pyrido [4,3-b ] indole (500 mg,1.90 mmol) in anhydrous N, N-dimethylformamide (6 ml) at 0℃was added sodium hydride (60% in mineral oil) (380 mg,9.50 mmol), and the resulting mixture was stirred at room temperature for 30 minutes. Sodium 2-chloro-2, 2-difluoroacetate (580 mg,3.80 mmol) was then added and the resulting reaction mixture was stirred at 80 ℃ for 5 hours. The reaction mixture was quenched with water (30 ml) at 0 ℃ and extracted with ethyl acetate (30 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (eluting with 50% ethyl acetate in hexane) to give 5- (difluoromethyl) -7- (6-fluoropyridin-3-yl) -5H-pyrido [4,3-b ] indole as a yellow solid (35 mg, 6% yield).
According to the following schemes, 5- (difluoromethyl) -7- (6-fluoropyridin-3-yl) -5H-pyrido [4,3-b ] indole is converted to the final compound, 5- ((14- ((5- (5- (difluoromethyl) -5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) -2- (2, 6-dioxapiperidin-3-yl) isoindoline-1, 3-dione, using the procedure described above and conventional procedures known to those skilled in the art.
Compounds of formula (I) 138：1H NMR(400MHz,DMSO-d6):δ2.01-2.04(m,1H),2.56-2.67(m,2H),2.83-2.93(m,1H),3.52-3.59(m,12H),3.78(s,4H),4.29(s,2H),4.45(s,2H),5.11(d,J＝12.8Hz,1H),6.98(d,J＝8.8Hz,1H),7.34(d,J＝8.4Hz,1H),7.43(s,1H),7.76-7.83(m,3H),8.14-8.18(m,2H),8.36-8.50(m,2H),8.61-8.65(m,2H),9.49(s,1H),11.11(s,1H).(M+H)+ 788.5.
Synthetic schemes for exemplary Compound 139
2- (2, 6-Dioxopiperidin-3-yl) -5- ((14- ((3-fluoro-5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) isoindoline-1, 3-dione
Prepared according to the following protocol using the procedure described above and conventional procedures known to those skilled in the art.
Synthetic scheme for exemplary Compound 140
2- (2, 6-Dioxopiperidin-3-yl) -5- ((14- ((3-methyl-5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) isoindoline-1, 3-dione
Step1 2-fluoro-5-iodo-3-methylpyridine
A mixture of 6-fluoro-5-methylpyridin-3-amine (300 mg,2.4 mmol) in N, N-dimethylacetamide (10 ml) was added to potassium iodide (390 mg,2.4 mmol), iodine (306 g,1.2 mmol), cuprous iodide (I) (137 mg,0.72 mmol) and tert-butyl nitrite (1.7 g,14.4 mmol) and stirred at 90℃for 2 hours. The reaction mixture was quenched with water (30 ml) and extracted with ethyl acetate (20 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (eluting with 10% ethyl acetate in hexane) to give 2-fluoro-5-iodo-3-methylpyridine as a white solid (350 mg, 62% yield).
Using the above procedure and conventional procedures known to those skilled in the art, 2-fluoro-5-iodo-3-methylpyridine is converted to the final compound, 2- (2, 6-dioxopiperidin-3-yl) -5- ((14- ((3-methyl-5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) isoindoline-1, 3-dione according to the following protocol.
Synthetic schemes for exemplary Compound 141
2- (2, 6-Dioxopiperidin-3-yl) -5- ((6- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyrimidin-2-yl) hex-5-yn-1-yl) oxy) isoindoline-1, 3-dione
Prepared according to the following protocol using the procedure described above and conventional procedures known to those skilled in the art.
In addition, compound 151 was prepared from compound 141 using the hydrogenation procedure previously described for the conversion of compound 102 to compound 110.
Synthetic schemes for exemplary Compound 142
2- (2, 6-Dioxopiperidin-3-yl) -5- ((1- (3- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) -3- (trifluoromethyl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yn-1-yl) azetidin-3-yl) oxy) isoindoline-1, 3-dione
Prepared according to the following protocol using the procedure described above and conventional procedures known to those skilled in the art.
Synthetic scheme for exemplary Compound 143
2- (2, 6-Dioxopiperidin-3-yl) -5- ((14- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) -6- (trifluoromethyl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) isoindoline-1, 3-dione
Step 1 6-chloro-3-iodo-2- (trifluoromethyl) pyridine
To a solution of lithium diisopropylamide (2M in THF, 3.03 mmol) in tetrahydrofuran (15 ml) was added a solution of 2-chloro-6- (trifluoromethyl) pyridine (500 mg,2.75 mmol) in tetrahydrofuran (5 ml) under nitrogen atmosphere at-65 ℃. The dark brown solution was stirred at-65 ℃ for 30 minutes. A solution of iodine (0.7 g,2.75 mmol) in tetrahydrofuran (5 ml) was added to the reaction mixture at-65℃over 20 minutes. After stirring for an additional 20 minutes at the same temperature, the reaction mixture was quenched with hydrochloric acid (2 m,6 ml) at 0 ℃ and stirred for 20 minutes. The reaction mixture was extracted with ethyl acetate (30 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (eluting with 1% ethyl acetate in hexane) to give 6-chloro-3-iodo-2- (trifluoromethyl) pyridine (316 mg, yield 37%) as a brown oil.
Using the above procedure and conventional procedures known to those skilled in the art, 6-chloro-3-iodo-2- (trifluoromethyl) pyridine was converted to the final compound, 2- (2, 6-dioxopiperidin-3-yl) -5- ((14- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) -6- (trifluoromethyl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) isoindoline-1, 3-dione according to the following protocol.
Synthetic schemes for exemplary Compound 146
2- (2, 6-Dioxopiperidin-3-yl) -5- ((6- (6- (3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) propoxy) pyridin-3-yl) hex-5-yn-1-yl) oxy) isoindoline-1, 3-dione
Prepared according to the following protocol using the procedure described above and conventional procedures known to those skilled in the art.
Synthetic schemes for exemplary Compound 152
2- (2, 6-Dioxopiperidin-3-yl) -5- ((1- (3- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) prop-2-yn-1-yl) azetidin-3-yl) oxy) isoindoline-1, 3-dione
Prepared according to the following protocol using the procedure described above and conventional procedures known to those skilled in the art.
Synthetic schemes for exemplary Compound 150
Step 1 2- [5- (3-Benzyloxycyclobutoxy) -2, 2-difluoro-pentoxy ] tetrahydropyran
To a solution of 3-benzyloxycyclobutanol (2.59 g,14.53mmol,1.10 eq.) in N, N-dimethylformamide (100 mL) under nitrogen at 0℃was added sodium hydride (581 mg,14.53mmol, 60% in mineral oil, 1.10 eq.). The mixture was stirred at 0 ℃ for 0.5 hours, and a solution of (4, 4-difluoro-5-tetrahydropyran-2-yloxy-pentyl) 4-methylbenzenesulfonate (5.0 g,13.21mmol,1.00 eq.) in N, N-dimethylformamide (20 mL) was added dropwise at 0 ℃. The reaction mixture was stirred at 60 ℃ for 6 hours. The mixture was cooled to 25 ℃ and poured into ice water (w/w=1/1) (30 mL) and stirred for 15 minutes. The aqueous phase was extracted with ethyl acetate (100 mL. Times.3). The combined organic phases were washed with brine (100 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=1/0, 20/1) to give 2- [5- (3-benzyloxycyclobutoxy) -2, 2-difluoro-pentoxy ] tetrahydropyran (1.75 g,4.21mmol,32% yield, 92% purity) as a colorless oil.
Step2 3- (4, 4-difluoro-5-tetrahydropyran-2-yloxy-pentyloxy) cyclobutanol
To a solution of 2- [5- (3-benzyloxybutyloxy) -2, 2-difluoro-pentoxy ] tetrahydropyran (1.75 g,4.55mmol,1.00 eq.) in methanol (30 mL) under nitrogen was added palladium on activated carbon catalyst (1.0 g,10% purity). The suspension was degassed under vacuum and purged several times with hydrogen. The mixture was stirred under hydrogen (15 psi) at 25 ℃ for 16 hours. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate=10:1 to 1:1) to give 3- (4, 4-difluoro-5-tetrahydropyran-2-yloxy-pentoxy) cyclobutanol (1.2 g,4.08mmol,90% yield) as a colourless oil.
Step 3 5-bromo-2- [3- (4, 4-difluoro-5-tetrahydropyran-2-yloxy-pentoxy) cyclobutoxy ] pyridine
To a mixture of 3- (4, 4-difluoro-5-tetrahydropyran-2-yloxy-pentoxy) cyclobutanol (1.2 g,4.08mmol,1.00 eq.) and 5-bromopyridin-2-ol (1.06 g,6.12mmol,1.50 eq.) in toluene (60 mL) under nitrogen at 0 ℃ was added a portion of 1,1' - (azodicarbonyl) dipiperidine (1.54 g,6.12mmol,1.50 eq.) and tributylphosphine (1.24 g,6.12mmol,1.50 eq.). The mixture was stirred at 110 ℃ for 16 hours. The mixture was cooled to 25 ℃ and concentrated under reduced pressure at 45 ℃. The residue was poured into ice water (w/w=1/1) (30 mL) and stirred for 15 minutes. The aqueous phase was extracted with ethyl acetate (50 mL. Times.3). The combined organic phases were washed with brine (50 ml×2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=100/1, 50/1). 5-bromo-2- [3- (4, 4-difluoro-5-tetrahydropyran-2-yloxy-pentoxy) cyclobutoxy ] pyridine (1.36 g,3.02mmol,74.0% yield) was obtained as a yellow oil.
Step 4 5- [3- [ (5-bromo-2-pyridinyl) oxy ] cyclobutoxy ] -2, 2-difluoro-pent-1-ol
To a mixture of 5-bromo-2- [3- (4, 4-difluoro-5-tetrahydropyran-2-yloxy-pentoxy) cyclobutoxy ] pyridine (1.1 g,2.44mmol,1.00 eq.) in tetrahydrofuran (25 mL) under nitrogen was added one portion of hydrogen chloride (4 m,10mL,16.38 eq.). The mixture was then stirred at 25 ℃ for 1 hour. The mixture was poured into saturated sodium bicarbonate (20 mL) and stirred for 15 min. The aqueous phase was extracted with ethyl acetate (50 mL. Times.3). The combined organic phases were washed with brine (50 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=10/1, 5/1) to give 5- [3- [ (5-bromo-2-pyridinyl) oxy ] cyclobutoxy ] -2, 2-difluoro-pent-1-ol (700 mg,1.91mmol,78% yield) as a colorless oil.
Step 5 [5- [3- [ (5-bromo-2-pyridinyl) oxy ] cyclobutoxy ] -2, 2-difluoro-pentyl ] trifluoromethanesulfonic acid ester
To a mixture of 5- [3- [ (5-bromo-2-pyridinyl) oxy ] cyclobutoxy ] -2, 2-difluoro-pent-1-ol (400 mg,1.09mmol,1.00 eq.) and triethylamine (552 mg,5.46mmol,5.00 eq.) in dichloromethane (10 mL) under nitrogen at 0 ℃ was added trifluoromethanesulfonyl chloride (268 mg,2.18mmol,2.00 eq.). After the addition was complete, the reaction mixture was stirred at 25 ℃ for 1 hour. The mixture was concentrated in vacuo at 40 ℃. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=5/1) to give [5- [3- [ (5-bromo-2-pyridinyl) oxy ] cyclobutoxy ] -2, 2-difluoro-pentyl ] trifluoromethanesulfonate (460 mg,0.93mmol,85% yield) as a colorless oil.
Step 6 tert-butyl 6- [2- (2, 6-dioxo-3-piperidyl) -1, 3-dioxo-isoindolin-5-yl ] -2, 6-diazaspiro [3.3] heptane-2-carboxylic acid ester
To a mixture of 2- (2, 6-dioxo-3-piperidinyl) -5-fluoro-isoindoline-1, 3-dione (300 mg,1.09mmol,1.00 eq.) and tert-butyl 2, 6-diazaspiro [3.3] heptane-2-carboxylate; oxalic acid (317 mg,0.65mmol,0.60 eq.) in (methylsulfinyl) methane (5 mL) under nitrogen was added one portion of N, N-diisopropylethylamine (561 mg,4.34mmol,4.00 eq.). The mixture was heated to 120 ℃ and stirred for 16 hours. The mixture was poured into ice water (w/w=1/1) (30 mL) and stirred for 10 minutes. The aqueous phase was extracted with ethyl acetate (50 mL. Times.3). The combined organic phases were washed with brine (50 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with petroleum ether:ethyl acetate (1:1, 50 mL) to give tert-butyl 6- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxo-isoindolin-5-yl ] -2, 6-diazaspiro [3.3] heptane-2-carboxylate (420 mg,0.92mmol,85% yield) as a yellow solid.
Step 7 5- (2, 6-diazaspiro [3.3] heptan-2-yl) -2- (2, 6-dioxo-3-piperidinyl) isoindoline-1, 3-dione
Tert-butyl 6- [2- (2, 6-dioxo-3-piperidinyl) -1, 3-dioxo-isoindolin-5-yl ] -2, 6-diazaspiro
[3.3] Heptane-2-carboxylate (420 mg,0.92mmol,1.00 eq.) in trifluoroacetic acid (1 mL) and dichloromethane (10 mL) was stirred under nitrogen at 25℃for 1 hour. TLC showed the reaction was complete. The mixture was concentrated under reduced pressure at 45 ℃. The mixture was purified by semi-preparative reverse phase HPLC (column: phenomenex Synergi Max-RP 250 x 50mm x 10um; mobile phase: [ water (0.225% FA) -ACN ]; B%:5ACN% -30ACN%,15 min; 50% molecular) to give 5- (2, 6-diazaspiro [3.3] heptan-2-yl) -2- (2, 6-dioxo-3-piperidinyl) isoindoline-1, 3-dione formate (260 mg,0.64mmol,70% yield) as a yellow solid.
Step 8 5- [6- [5- [3- [ (5-bromo-2-pyridinyl) oxy ] cyclobutoxy ] -2, 2-difluoro-pentyl ] -2, 6-diazaspiro [3.3] heptane-2-yl ] -2- (2, 6-dioxo-3-piperidinyl) isoindoline-1, 3-dione
To a mixture of [5- [3- [ (5-bromo-2-pyridinyl) oxy ] cyclobutoxy ] -2, 2-difluoro-pentyl ] trifluoromethanesulfonate (460 mg,0.92mmol,1.00 eq.) and 5- (2, 6-diazaspiro [3.3] heptan-2-yl) -2- (2, 6-dioxo-3-piperidinyl) isoindoline-1, 3-dione formate (443 mg,1.11mmol,1.20 eq.) in acetonitrile (25 mL) and (methylsulfinyl) methane (5 mL) under nitrogen was added one portion of potassium carbonate (255 mg,1.85mmol,2.00 eq.). The mixture was stirred at 25 ℃ for 10 hours. LC-MS showed that [5- [3- [ (5-bromo-2-pyridinyl) oxy ] cyclobutoxy ] -2, 2-difluoro-pentyl ] trifluoromethanesulfonic acid ester was completely consumed and one major peak with the desired MS was detected. The suspension was filtered and concentrated in vacuo. The residue was diluted with ethyl acetate (100 mL), washed with brine (30 ml×3)), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=1/1, 1/3) to give 5- [6- [5- [3- [ (5-bromo-2-pyridinyl) oxy ] cyclobutoxy ] -2, 2-difluoro-pentyl ] -2, 6-diazaspiro [3.3] heptan-2-yl ] -2- (2, 6-dioxo-3-piperidinyl) isoindoline-1, 3-dione (320 mg,0.45mmol,49% yield) as a yellow solid.
Step 9 5- [6- [2, 2-difluoro-5- [3- [ [5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2-pyridinyl ] oxy ] cyclobutoxy ] pentyl ] -2, 6-diazaspiro [3.3] heptan-2-yl ] -2- (2, 6-dioxo-3-piperidinyl) isoindoline-1, 3-dione
A solution of 5- [6- [5- [3- [ (5-bromo-2-pyridinyl) oxy ] cyclobutoxy ] -2, 2-difluoro-pentyl ] -2, 6-diazaspiro [3.3] heptan-2-yl ] -2- (2, 6-dioxo-3-piperidinyl) isoindoline-1, 3-dione (200 mg,0.28mmol,1.00 eq.), 4, 5-tetramethyl-2- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,3, 2-dioxaborane (86 mg,0.34mmol,1.20 eq.), potassium acetate (55 mg,0.56mmol,2.00 eq.) and 1,1' -bis (diphenylphosphino) ferrocene-palladium (ii) dichloride dichloromethane complex (23 mg,0.02mmol,0.10 eq.) in dioxane (10 mL) is degassed and then heated to a total of 90℃under nitrogen for 2 hours. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by preparative TLC (dichloromethane: methanol=20:1) to give 5- [6- [2, 2-difluoro-5- [3- [ [5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2-pyridinyl ] oxy ] cyclobutoxy ] pentyl ] -2, 6-diazaspiro [3.3] heptan-2-yl ] -2- (2, 6-dioxo-3-piperidinyl) isoindoline-1, 3-dione as a yellow oil (200 mg,0.26mmol,94% yield).
Step 10 5- [6- [2, 2-difluoro-5- [3- [ [5- (5-methylpyrido [4,3-b ] indol-7-yl) -2-pyridinyl ] oxy ] cyclobutoxy ] pentyl ] -2, 6-diazaspiro [3.3] heptan-2-yl ] -2- (2, 6-dioxo-3-piperidinyl) isoindoline-1, 3-dione
5- [6- [2, 2-Difluoro-5- [3- [ [5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2-pyridinyl ] oxy ] cyclobutoxy ] pentyl ] -2, 6-diazaspiro [3.3] heptan-2-yl ] -2- (2, 6-dioxo-3-piperidinyl) isoindoline-1, 3-dione (200 mg,0.26mmol,1.00 eq.), 7-bromo-5-methyl-pyrido [4,3-b ] indole (69 mg,0.26mmol,1.00 eq.), sodium carbonate (56 mg,0.53mmol,2.00 eq.) and 1,1' bis (diphenylphosphino) ferrocene-palladium dichloride (ii) dichloromethane complex (21 mg,0.02mmol,0.10 eq.) in N, N-dimethylformamide (5 mL) and water (0.5 mL) were degassed and then heated at nitrogen for a total of 2℃under nitrogen conditions of 90 ℃. LCMS showed the reaction was complete. The mixture was cooled to 25 ℃ and filtered. The residue was diluted with ethyl acetate (50 mL), washed with brine (30 ml×3), dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was purified by semi-preparative reverse phase HPLC (18-48% acetonitrile +0.225% formic acid in water over 10 minutes). The collected fractions were then concentrated to remove most of the acetonitrile. The solution was lyophilized. 5- [6- [2, 2-difluoro-5- [3- [ [5- (5-methylpyrido [4,3-b ] indol-7-yl) -2-pyridinyl ] oxy ] cyclobutoxy ] pentyl ] -2, 6-diazaspiro [3.3] heptan-2-yl ] -2- (2, 6-dioxo-3-piperidinyl) isoindoline-1, 3-dione formate (21.6 mg,0.02mmol,9% yield, 95% purity) was obtained as a yellow solid.
1H NMR:(400MHz,DMSO-d6)δ:10.95(s,1H),9.14(br s,1H),8.15(s,1H),7.52(d,J＝9.0Hz,1H),7.18-7.04(m,5H),6.83(d,J＝6.7Hz,2H),6.65(d,J＝8.5Hz,1H),6.61(s,1H),6.54-6.47(m,3H),6.26(d,J＝8.5Hz,2H),5.05(dd,J＝5.0,13.3Hz,1H),4.38-4.26(m,1H),4.24-4.11(m,1H),3.78(br t,J＝6.5Hz,4H),3.54-3.31(m,3H),3.03-2.83(m,8H),2.62-2.52(m,3H),2.47-2.31(m,1H),2.21-2.04(m,3H),2.01-1.87(m,3H),1.71(br d,J＝10.7Hz,2H).(M+H)+ 804.5.
Synthetic schemes for exemplary Compound 153
2- (2, 6-Dioxopiperidin-3-yl) -5- (3, 3-trifluoro-2- ((5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pentyl) oxy) propyl) azetidin-1-yl) isoindoline-1, 3-dione
Prepared according to the following protocol using the procedure described above and conventional procedures known to those skilled in the art.
The following compound 154 was prepared using the procedure of compound 153.
Synthetic schemes for exemplary Compound 155
2- (2, 6-Dioxopiperidin-3-yl) -5- (3- ((5- (2- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) ethoxy) pyridin-2-yl) oxy) azetidin-1-yl) isoindoline-1, 3-dione
Prepared according to the following protocol using the procedure described above and conventional procedures known to those skilled in the art.
Synthetic schemes for exemplary Compound 156
2- (2, 6-Dioxopiperidin-3-yl) -5- (3- (3- (5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) propoxy) azetidin-1-yl) isoindoline-1, 3-dione
Prepared according to the schemes below and using the procedures described above and conventional procedures known to those skilled in the art.
Synthetic scheme for exemplary Compound 157
2- (2, 6-Dioxopiperidin-3-yl) -5- (4- ((2- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutane-1-carbonyl) -2-azaspiro [3.3] heptan-6-yl) oxy) butoxy) isoindoline-1, 3-dione
Step 1 (1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutanecarboxylic acid
To a solution of (1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutanecarbaldehyde (70 mg,0.20 mmol) in tetrahydrofuran (1 ml) and water (1 ml) was added sodium chlorite (62 mg,0.63 mmol), anhydrous sodium dihydrogen phosphate (168 mg,1.08 mmol) and 2-methylbutan-2-ene (233 mg,3.33 mmol), and the mixture was stirred at room temperature overnight. TLC showed the reaction was complete. The reaction mixture was diluted with dichloromethane (20 ml), washed with water (10 ml x 3), brine (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude (1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutanecarboxylic acid as a yellow solid.
(1 R,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutanecarboxylic acid is converted to the final compound, 2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((2- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutane-1-carbonyl) -2-azaspiro [3.3] heptan-6-yl) oxy) isoindoline-1, 3-dione, according to the protocol below and using the procedure described above for compound 153.
Synthetic schemes for exemplary Compound 158
2- (2, 6-Dioxopiperidin-3-yl) -5- (2- ((6- (4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) piperidin-1-yl) pyridazin-4-yl) oxy) ethoxy) isoindoline-1, 3-dione
Step 15- (2- (benzyloxy) ethoxy) -3-chloropyridazine
To a stirred solution of 2- (benzyloxy) ethanol (440 mg,2.895 mmol) and 3, 5-dichloropyridazine (428 mg,2.895 mmol) in 1-methyl-2-pyrrolidone (5 ml) at 0 ℃ was added sodium hydride (60% in oil) (277 mg,8.68 mmol). The mixture was then stirred at room temperature for 1 hour. The reaction mixture was quenched with aqueous ammonium chloride (15 ml) at 0 ℃ and extracted with ethyl acetate (20 ml x 3). The organic layer was washed with brine (20 ml×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash column chromatography (eluting with 15% ethyl acetate in hexane) to give 5- (2- (benzyloxy) ethoxy) -3-chloropyridazine (680 mg,89% yield) as a light brown oil.
Step 2 (1 r,3 r) -3- ((1- (5- (2- (benzyloxy) ethoxy) pyridazin-3-yl) piperidin-4-yl) oxy) cyclobutanol
To a mixture of 5- (2- (benzyloxy) ethoxy) -3-chloropyridazine (240 mg,0.910 mmol) and (1 r,3 r) -3- (piperidin-4-yloxy) cyclobutanol (155 mg,0.910 mmol) under nitrogen [ prepared via hydrogenation of (1 r,3 r) -3- ((1-benzylpiperidin-4-yl) oxy) cyclobutan-1-ol as described in step 5 of compound 65, but in the absence of di-tert-butyl carbonate ] in toluene (5 ml) was added Pd 2(dba)3 (83 mg,0.091 mmol), (+/-) -2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl (56 mg,0.091 mmol) and cesium carbonate (739 mg,2.27 mmol). The mixture was then heated to 90 ℃ overnight. TLC showed the reaction was complete. The reaction mixture was extracted with ethyl acetate (30 ml x 3). The organic layer was washed with brine (10 ml×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash column chromatography (eluting with 8% ethyl acetate in hexane) to give (1 r,3 r) -3- ((1- (5- (2- (benzyloxy) ethoxy) pyridazin-3-yl) piperidin-4-yl) oxy) cyclobutanol (135 mg,38% yield) as a pale yellow oil.
(1 R,3 r) -3- ((1- (5- (2- (benzyloxy) ethoxy) pyridazin-3-yl) piperidin-4-yl) oxy) cyclobutanol is converted to the final compound, 2- (2, 6-dioxopiperidin-3-yl) -5- (2- ((6- (4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) piperidin-1-yl) pyridazin-4-oxy) ethoxy) isoindoline-1, 3-dione, according to the scheme below and using the procedure described above and conventional procedures known to those skilled in the art.
Synthetic schemes for exemplary Compounds 159 and 160
2- (2, 6-Dioxopiperidin-3-yl) -5- (3- ((3- (5- ((1 s,3 s) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) prop-2-yn-1-yl) oxy) azetidin-1-yl) isoindoline-1, 3-dione
2- (2, 6-Dioxopiperidin-3-yl) -5- (3- (3- (5- ((1 s,3 s) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pyridin-2-yl) propoxy) azetidin-1-yl) isoindoline-1, 3-dione
Prepared according to the schemes below and using the procedures described above and conventional procedures known to those skilled in the art.
Synthetic schemes for exemplary Compound 161
2- (2, 6-Dioxopiperidin-3-yl) -5- (3- (2- (2- (2- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) ethoxy) azetidin-1-yl) isoindoline-1, 3-dione
Prepared according to the schemes below and using the procedures described above and conventional procedures known to those skilled in the art.
Based on the general procedure for compound 163, and using conventional methods known to those skilled in the art, additional compounds 162, 165, 178, 181 and 182 are prepared.
Synthetic schemes for exemplary Compounds 165 and 166
5- ((5- ((1 R,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutan-1-carbonyl) piperidin-4-yl) oxy) pentyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
5- ((5- ((1 S,3 s) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutan-1-carbonyl) piperidin-4-yl) oxy) pentyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
Prepared according to the schemes below and using the procedures described above and conventional procedures known to those skilled in the art.
Synthetic schemes for exemplary Compounds 167 and 168
2- (2, 6-Dioxopiperidin-3-yl) -5- (3- ((3- (5- (3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) propoxy) pyridin-2-yl) prop-2-yn-1-yl) oxy) azetidin-1-yl) isoindoline-1, 3-dione
2- (2, 6-Dioxopiperidin-3-yl) -5- (3- (3- (3- (5- (3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) propoxy) pyridin-2-yl) propoxy) azetidin-1-yl) isoindoline-1, 3-dione
Prepared according to the schemes below and using the procedures described above and conventional procedures known to those skilled in the art.
Synthetic scheme for exemplary Compound 169
2- (2, 6-Dioxopiperidin-3-yl) -5- (3- (3- ((3- (((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) methyl) oxetan-3-yl) methoxy) propoxy) azetidin-1-yl) isoindoline-1, 3-dione
Prepared according to the schemes below and using the procedures described above and conventional procedures known to those skilled in the art.
Synthetic schemes for exemplary Compound 174
2- (2, 6-Dioxopiperidin-3-yl) -5- (4- ((3- (((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) methyl) bicyclo [1.1.1] pent-1-yl) methoxy) butoxy) isoindoline-1, 3-dione
Step1 bicyclo [1.1.1] pentane-1, 3-diyl dimethanol
To a solution of dimethyl bicyclo [1.1.1] pentane-1, 3-dicarboxylate (500 mg,2.72 mmol) in tetrahydrofuran (5 ml) was added lithium aluminum hydride (319 mg,10.87 mmol) at 0 ℃, and the resulting mixture was stirred at room temperature for 2 hours. TLC showed the reaction was complete. The reaction mixture was quenched with water (1 ml), sodium hydroxide (2 ml,10% aqueous solution) and water (1 ml). The solid was removed by filtration, and the filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give bicyclo [1.1.1] pentane-1, 3-diyldimethanol (256 mg crude, yield 70%) as a pale yellow oil.
The bicyclo [1.1.1] pentane-1, 3-diyl-dimethanol was converted to the final compound, 2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((3- (((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) methyl) bicyclo [1.1.1] pent-1-yl) methoxy) butoxy) isoindoline-1, 3-dione according to the scheme below, and using the procedure described above and conventional procedures known to those skilled in the art.
Synthetic scheme for exemplary Compound 175
2- (2, 6-Dioxopiperidin-3-yl) -5- ((5- ((3- (3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) azetidine-1-carbonyl) bicyclo [1.1.1] pent-1-yl) methoxy) pentyl) oxy) isoindoline-1, 3-dione
Step 1 3- (hydroxymethyl) bicyclo [1.1.1] pentane-1-carboxylate
To a solution of dimethyl bicyclo [1.1.1] pentane-1, 3-dicarboxylate (1 g,5.43 mmol) in tetrahydrofuran (10 ml) was added lithium borohydride (120 mg,5.43 mmol) at 0℃under nitrogen. The mixture was allowed to warm to room temperature and stirred at room temperature for 5 hours. The mixture was quenched with aqueous hydrochloric acid (1N) to pH 3-4 and extracted with dichloromethane (10 ml. Times.2). The organic layers were combined, washed with brine (10 ml), dried over sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluting with 20-33% ethyl acetate in hexane) to give methyl 3- (hydroxymethyl) bicyclo [1.1.1] pentane-1-carboxylate (400 mg, 47%) as a colourless oil.
The 3- (hydroxymethyl) bicyclo [1.1.1] pentane-1-carboxylate was converted to the final compound, 2- (2, 6-dioxopiperidin-3-yl) -5- ((5- ((3- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) azetidine-1-carbonyl) bicyclo [1.1.1] pent-1-yl) methoxy) pentyl) oxy) isoindoline-1, 3-dione according to the scheme below, and using the procedures described above and conventional procedures known to those skilled in the art.
Synthetic scheme for exemplary Compound 176
5- (3- (3- (3- ((1 R,3 r) -3- ((5- (8, 9-difluoro-5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) propoxy) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
Prepared according to the schemes below, and using the procedures described above for compound 104 (in modified order) and conventional procedures known to those skilled in the art.
Synthetic schemes for exemplary Compound 177
3- (5- (3- (3- (3- ((1 R,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) propoxy) azetidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione
Step 15- (3- (3- (3- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) -3- (trifluoromethyl) pyridin-2-yl) oxy) cyclobutoxy) propoxy) azetidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
A mixture of 7- (6- ((1 r,3 r) -3- (3- (3- (azetidin-3-yloxy) propoxy) cyclobutoxy) pyridin-3-yl) -5-methyl-5H-pyrido [4,3-b ] indole (crude, 0.390 mmol) [ prepared as described for compound 104 ], N-ethyl-N-isopropyl-2-amine (86 mg,1.17 mmol) and methyl 2-cyano-4-fluorobenzoate (90 mg, 0.4638 mmol) in 1-methyl-2-pyrrolidone (3 ml) was stirred at 90℃for 16 hours. TLC showed the reaction was complete. The reaction mixture was partitioned between ethyl acetate (20 ml) and water (30 ml). The organic layer was collected, washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by flash column chromatography on silica gel (eluting with 2-4% methanol in dichloromethane) to give 5- (3- (3- ((1 r,3 r) -3- ((5- (5H-pyrido [4,3-b ] indol-7-yl) -3- (trifluoromethyl) pyridin-2-yl) oxy) cyclopropoxy) propoxy) propan-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (160 mg, 61%) as a pale yellow oil.
Step 2 methyl 2-formyl-4- (3- (3- (3- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ]) methylindol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) propoxy) azetidin-1-yl) benzoate
To a mixture of methyl 2-cyano-4- (3- (3- (3- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) propoxy) azetidin-1-yl) benzoate (160 mg,0.237 mmol) in pyridine (3 ml) -water (1.5 ml) -acetic acid (1.5 ml) was added sodium hypophosphite (125 mg, 1.178 mmol) and raney nickel (85% in water) (300 mg). The resulting mixture was stirred at 50 ℃ for 2 hours. The mixture was diluted with ethyl acetate (30 ml), washed with water (30 ml×2), dilute hydrochloric acid solution (1 n,30 ml), brine (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluting with 2-5% methanol in dichloromethane) to give methyl 2-formyl-4- (3- (3- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclopropoxy) cyclobutoxy) azetidin-1-yl) benzoate (90 mg, yield 56%) as a brown oil.
Step 3- (5- (3- (3- (3- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) propoxy) azetidin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione
A mixture of 3-aminopiperidine-2, 6-dione (32 mg, 0.199mmol), N-ethyl-N-isopropyl-2-amine (34 mg, 0.199mmol), acetic acid (0.5 ml) and methyl 2-formyl-4- (3- (3- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) oxy) pyridin-2-yl) oxy) cyclopropoxy) propoxy) azetidin-1-yl) benzoate (90 mg,0.133 mmol) in methanol (5 ml) was stirred at room temperature for 15 minutes. Sodium cyanoborohydride (16 mg,0.400 mmol) was then added and stirred at room temperature overnight. TLC showed the reaction was complete. The reaction mixture was partitioned between dichloromethane (30 ml) and water (10 ml), the organic layer was collected, washed with brine (10 ml×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by preparative TLC (8% methanol in ethyl acetate) to give the title compound as a white solid (50 mg, yield 50%).
1H NMR(400MHz,DMSO-d6):δ1.71-1.80(m,4H),1.90-1.93(m,1H),2.28-2.37(m,3H),2.40-2.44(m,2H),2.56-2.57(m,1H),2.83-2.92(m,1H),3.37(t,J＝6.0Hz,2H),3.43-3.48(m,6H),3.67-3.70(m,2H),3.95(s,3H),4.11-4.19(m,4H),4.23-4.27(m,1H),4.42-4.44(m,1H),4.99-5.03(m,1H),5.31-5.34(m,1H),6.46-6.49(m,2H),6.94(d,J＝8.8Hz,1H),7.47(d,J＝8.4Hz,1H),7.60-7.63(m,2H),7.97(s,1H),8.17-8.20(m,1H),8.32(d,J＝8.0Hz,1H),8.50(d,J＝6.0Hz,1H),8.64(d,J＝2.0Hz,1H),9.37(s,1H),10.92(s,1H).(M+H)+ 759.6.
Synthetic schemes for exemplary Compound 184
2- (2, 6-Dioxopiperidin-3-yl) -5- ((7- (3- (3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) azetidine-1-carbonyl) bicyclo [1.1.1] pent-1-yl) heptyl) oxy) isoindoline-1, 3-dione
Step 1 (6- (benzyloxy) hexyl) triphenylphosphine onium bromide
A mixture of (((6-bromohexyl) oxy) methyl) benzene (2.7 g,10 mmol) and triphenylphosphine (2.6 g,10 mmol) in acetonitrile (10 ml) was stirred under reflux for 40 hours. The reaction mixture was allowed to cool to room temperature, and concentrated under reduced pressure to give (6- (benzyloxy) hexyl) triphenylphosphine onium bromide as a colorless oil (5 g, yield: 94%).
Step2 methyl 3-formylbicyclo [1.1.1] pentane-1-carboxylate
To a stirred solution of methyl 3- (hydroxymethyl) bicyclo [1.1.1] pentane-1-carboxylate (156 mg,1 mmol) in dichloromethane (10 ml) at 0deg.C was added dess-martin periodate (840 mg,2.0 mmol). The resulting reaction mixture was allowed to warm to room temperature and stirred at that temperature for an additional 1 hour. The reaction mixture was quenched with aqueous sodium sulfite (10 ml) and extracted with dichloromethane (20 ml x 2), washed with brine (20 ml x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluting with 20% ethyl acetate in hexane) to give methyl 3-formylbicyclo [1.1.1] pentane-1-carboxylate (110 mg, 70% yield) as a colourless oil.
Step 3 methyl 3- (7- (benzyloxy) hept-1-en-1-yl) bicyclo [1.1.1] pentane-1-carboxylate
To a solution of (6- (benzyloxy) hexyl) triphenylphosphine onium bromide (373 mg,0.70 mmol) in anhydrous tetrahydrofuran (6 ml) at-20 ℃ was added n-butyllithium (2.5M hexane solution) (0.28 ml,0.7 mmol) dropwise, and the resulting mixture was stirred at the same temperature for 30 minutes. A solution of methyl 3-formylbicyclo [1.1.1] pentane-1-carboxylate (90 mg,0.58 mmol) in anhydrous tetrahydrofuran (1 ml) was added dropwise. The resulting reaction mixture was slowly warmed to room temperature and stirred at the same temperature for 30 minutes. The reaction mixture was quenched with water (10 ml) at 0 ℃ and extracted with ethyl acetate (20 ml x 2). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (eluting with 10% ethyl acetate in hexane) to give methyl 3- (7- (benzyloxy) hept-1-en-1-yl) bicyclo [1.1.1] pentane-1-carboxylate (56 mg, 29% yield) as a colourless oil.
Methyl 3- (7- (benzyloxy) hept-1-en-1-yl) bicyclo [1.1.1] pentane-1-carboxylate was converted to the final compound, 2- (2, 6-dioxopiperidin-3-yl) -5- ((7- (3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) azetidine-1-carbonyl) bicyclo [1.1.1] pent-1-yl) hept-oxy) isoindoline-1, 3-dione according to the scheme below, and using the procedures described above and conventional procedures known to those skilled in the art.
Synthetic scheme for exemplary Compound 185
(2S, 4R) -N- (2- (2- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) ethoxy) -4- (4-methylthiazol-5-yl) benzyl) -4-hydroxy-1- ((S) -3-methyl-2- (1-oxoisoindolin-2-yl) butanoyl) pyrrolidine-2-carboxamide
Prepared according to the schemes below and using the procedures described above and conventional procedures known to those skilled in the art.
Compounds 186, 187, 196, 201 were prepared using a procedure similar to compound 185.
Synthetic schemes for exemplary Compound 193
2- (2, 6-Dioxopiperidin-3-yl) -5- (3- (3- (2- (6- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -2-azaspiro [3.3] heptan-2-yl) -2-oxoethoxy) propoxy) azetidin-1-yl) isoindoline-1, 3-dione
Prepared according to the schemes below and using the procedures described above and conventional procedures known to those skilled in the art.
Synthetic scheme for exemplary Compound 195
5- ((14- ((5- (4-Chloro-5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
Step1 3-bromo-5-chloropyridin-4-amine
To a solution of 3-chloropyridin-4-amine (10 g,77.78 mmol) in acetonitrile (100 ml) was added N-bromosuccinimide (14.5 g,81.67 mmol) at room temperature and the resulting mixture was stirred overnight at 60℃under nitrogen. The reaction mixture was quenched with water (50 ml) and extracted with ethyl acetate (50 ml x 2). The combined organic layers were washed with brine (50 ml x 2), dried over anhydrous sodium sulfate and concentrated to give a residue which was purified by silica gel flash chromatography (eluting with 20-50% ethyl acetate in hexanes) to give 3-bromo-5-chloropyridin-4-amine as a white solid (8.8 g, 54% yield).
Step 2 3- (4-bromophenyl) -5-chloropyridin-4-amine
A mixture of 3-bromo-5-chloropyridin-4-amine (5 g,24.10 mmol), bis (pinacolato) diboron (12 g,48320 mmol), potassium acetate (4.7 g,48.20 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (3.5 g,4.82 mmol) in dioxane (100 ml) was stirred overnight at 90℃under nitrogen. TLC showed the reaction was complete. To the mixture solution were added 1, 4-dibromobenzene (11.4 g,48.20 mmol), potassium carbonate (6.7 g,48.20 mmol) and water (30 ml). Tetrakis (triphenylphosphine) palladium (1.4 g,1.21 mmol) was added and the mixture stirred under nitrogen at 90 ℃ overnight. The reaction mixture was filtered and the filtrate was partitioned between ethyl acetate (100 ml) and water (100 ml), the organic layer was washed with brine (20 ml x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluting with 20-50% ethyl acetate in hexanes) to give 3- (4-bromophenyl) -5-chloropyridin-4-amine (2.3 g, 34%) as a yellow solid.
Step 3 4-azido-3- (4-bromophenyl) -5-chloropyridine
To a solution of 3- (4-bromophenyl) -5-chloropyridin-4-amine (2.5 g,8.8 mmol) in 2, 2-trifluoroacetic acid (10 ml) at 0℃was added sodium nitrite (1.5 g,22.0 mmol) over 20 min, and the reaction mixture was stirred at 0℃for 1 h. Sodium azide (1.43 g,22.0 mmol) was added to the reaction mixture at 0 ℃, and the resulting mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was basified with sodium carbonate to pH 8 and partitioned between ethyl acetate (30 ml) and water (50 ml). The organic layer was collected and the aqueous layer was extracted with ethyl acetate (30 ml x 2). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluting with 30% ethyl acetate in hexane) to give 4-azido-3- (4-bromophenyl) -5-chloropyridine as a yellow solid (850 mg, 31% yield).
Step 4:
A mixture of 4-azido-3- (4-bromophenyl) -5-chloropyridine (850 mg,2.75 mmol) in decalin (10 ml) was stirred in a sealed tube at 150℃for 10 hours. After cooling to room temperature, the reaction mixture was triturated with hexane (20 ml). The resulting solid was collected by filtration and dried under vacuum to give 7-bromo-4-chloro-5H-pyrido [4,3-b ] indole (600 mg, 77% yield) as a yellow solid, which was used in the next step without further purification.
7-Bromo-4-chloro-5H-pyrido [4,3-b ] indole was converted to the final compound, 5- ((14- ((5- (4-chloro-5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione according to the following protocol, and using the procedure described above and conventional procedures known to those skilled in the art.
Synthetic schemes for exemplary Compound 197
5- (6- ((2, 2-Difluoro-5- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) pentyl) oxy) -2-azaspiro [3.3] heptan-2-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
Prepared according to the schemes below and using the procedures described above and conventional procedures known to those skilled in the art.
Synthetic schemes for exemplary Compound 199
3- ((4- ((2- (2, 6-Dioxopiperidin-3-yl) -1, 3-Dioxoisoindolin-5-yl) oxy) butoxy) methyl) -N-methyl-N- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutyl) bicyclo [1.1.1] pentane-1-carboxamide
Prepared according to the schemes below and using the procedures described above and conventional procedures known to those skilled in the art.
Synthetic scheme for exemplary Compound 202
2- ((1- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidin-3-yl) methoxy) -N-methyl-N- (3- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) propyl) acetamide
Prepared according to the schemes below and using the procedures described above and conventional procedures known to those skilled in the art.
Synthetic schemes for exemplary Compound 203
2- ((14- ((2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) -5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) nicotinonitrile
Prepared according to the schemes below and using the procedures described above and conventional procedures known to those skilled in the art.
Synthetic scheme for exemplary Compound 207
5- ((5- (Benzo [4,5] imidazo [1,2-a ] pyrimidin-2-yl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
Step 1 (E) -1, 1-trichloro-4-ethoxy-but-3-en-2-one
To a solution of 2, 2-trichloroacetyl chloride (31.52 g,173.36mmol,19mL,1 eq.) was added dropwise vinyl diethyl ether (25 g,346.71mmol,33mL,2 eq.) at 0 ℃. After the addition, the mixture was stirred at this temperature for 5 hours, and then the mixture was warmed to 25 ℃ for 16 hours. The mixture was stirred under reduced pressure at 130 ℃ to evaporate the gas (hydrogen chloride) to form a deep black solution. The process takes 1 hour or until no gas comes out. The residue was concentrated under reduced pressure. The crude product (E) -1, 1-trichloro-4-ethoxy-but-3-en-2-one (39.3 g, crude) was obtained as a black oil.
Step 2- (trichloromethyl) pyrimido [1,2-a ] benzimidazole
To a mixture of (E) -1, 1-trichloro-4-ethoxy-but-3-en-2-one (39.2 g,180.25mmol,1.09 eq.) and 1H-benzimidazol-2-amine (22 g,165.23mmol,1 eq.) in toluene (500 mL) at 25℃under nitrogen was added one portion of triethylamine (20.06 g,198.27mmol,27mL,1.2 eq.). The mixture was stirred at 120 ℃ for 4 hours. The mixture was cooled to 25 ℃ and concentrated under reduced pressure at 55 ℃. The crude product 2- (trichloromethyl) pyrimido [1,2-a ] benzimidazole (56.3 g, crude) was obtained as a brown solid.
Step 3 pyrimido [1,2-a ] benzimidazol-2-ol
To a mixture of 2- (trichloromethyl) pyrimido [1,2-a ] benzimidazole (55.2 g,192.64mmol,1 eq.) in acetonitrile (950 mL) under nitrogen at 20℃was added a solution of sodium hydroxide (10.2 g,255.02mmol,1.32 eq.) in water (246 mL). The mixture was stirred at 100 ℃ for 2 hours. The mixture was cooled to 25 ℃ and concentrated under reduced pressure at 55 ℃. Ice was added to the resulting residue, and the pH of the solution was adjusted to 8 with hydrochloric acid (1 n,130 ml). The solid was filtered and dried under high vacuum. The filtrate was cooled to 10 ℃ and some precipitate formed, and the filter cake was collected by filtration and concentrated under reduced pressure to give a residue. The compound pyrimido [1,2-a ] benzimidazol-2-ol (9.3 g,50.22mmol,26% yield) was obtained as a yellow solid and the crude product (about 7.3 g) was obtained.
Step 4 2-bromopyrimido [1,2-a ] benzimidazole
To a solution of pyrimido [1,2-a ] benzimidazol-2-ol (0.5 g,2.70mmol,1 eq.) in 1, 1-dichloroethane (18 mL) and N, N-dimethylformamide (0.18 mL) under nitrogen at 20℃was added one portion of phosphorus tribromide (1.55 g,5.40mmol,2 eq.). The mixture was stirred at 100 ℃ for 6 hours. The mixture was cooled to 25 ℃ and concentrated under reduced pressure at 45 ℃. The residue was poured into ice water (w/w=1/1, 30 ml) and stirred for 10 minutes. The aqueous phase was adjusted to ph=8 with a saturated aqueous solution of sodium bicarbonate. During this time, some precipitate formed. The filter cake was collected by filtration and dried under high vacuum. The crude product 2-bromopyrimido [1,2-a ] benzimidazole (0.65 g, crude) was obtained as a yellow solid.
2-Bromopyrimido [1,2-a ] benzimidazole is converted to the final compound, 5- ((14- ((5- (benzo [4,5] imidazo [1,2-a ] pyrimidin-2-yl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) oxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione according to the scheme below and using the procedures described above and conventional procedures known to those skilled in the art.
Synthetic schemes for exemplary Compound 208
2- (2, 6-Dioxopiperidin-3-yl) -5- (2- (2- (2- (2- ((1- (5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) azetidin-3-yl) oxy) ethoxy) isoindoline-1, 3-dione
Prepared according to the schemes below and using the procedures described above and conventional procedures known to those skilled in the art.
Synthetic scheme for exemplary Compound 209
2- (2, 6-Dioxopiperidin-3-yl) -5- (2- (2- ((3- (((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) methyl) bicyclo [1.1.1] pent-1-yl) methoxy) ethoxy) isoindoline-1, 3-dione
Prepared according to the schemes below and using the procedures described above and conventional procedures known to those skilled in the art.
Synthetic scheme for exemplary Compound 210
2- (2, 6-Dioxopiperidin-3-yl) -5- ((15- (4- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) piperazin-1-yl) -3,6,9, 12-tetraoxapentadecyl) oxy) isoindoline-1, 3-dione
Step 1 t-butyl 4- (5-methylpyrido [4,3-b ] indol-7-yl) piperazine-1-carboxylate
To a solution of 7-bromo-5-methyl-pyrido [4,3-b ] indole (1 g,3.83mmol,1 eq.) and tert-butylpiperazine-1-carboxylate (2.14 g,11.49mmol,3 eq.) in dioxane (20 mL) under nitrogen was added (±) -2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl (71 mg,0.11mmol,0.03 eq.), cesium carbonate (3.74 g,11.49mmol,3 eq.) and palladium (II) acetate (86 mg,0.38mmol,0.1 eq.) followed by degassing under vacuum and purging with nitrogen three times. The mixture was stirred at 100 ℃ for 16 hours. The reaction mixture was concentrated to remove the solvent, then extracted with ethyl acetate (80 ml x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=2/1 to dichloromethane/methanol=10/1) to give a crude product, which was purified by semi-preparative reverse phase HPLC (column: phenomenex luna C: 250 x 50mm x 10um; mobile phase: [ water (0.225% fa) -ACN ];:% B: 27% -52%,30;79% min). Tert-butyl 4- (5-methylpyrido [4,3-b ] indol-7-yl) piperazine-1-carboxylate (700 mg,1.91mmol,49% yield) was obtained as a white solid.
Step 2 5-methyl-7-piperazin-1-yl-pyrido [4,3-b ] indole
To a solution of tert-butyl 4- (5-methylpyrido [4,3-b ] indol-7-yl) piperazine-1-carboxylate (700 mg,1.91mmol,1 eq.) in dichloromethane (4 mL) was added hydrochloric acid/dioxane (4 m,8mL,16.75 eq.) followed by stirring at 25 ℃ for 1 hour. TLC (dichloromethane/methanol=10/1) showed complete consumption of starting material. The reaction mixture was concentrated to give a residue. 5-methyl-7-piperazin-1-yl-pyrido [4,3-b ] indole (580 mg, crude, HCl) was obtained as a white solid without any purification.
Step 3:
To a solution of 5-methyl-7-piperazin-1-yl-pyrido [4,3-b ] indole (366 mg,1.21mmol,1 eq, HCl) and dimethyl 4- [2- [2- [2- [2- [3- (p-toluenesulfonyloxy) propoxy ] ethoxy ] benzene-1, 2-dicarboxylic acid ester (725 mg,1.21mmol,1 eq) [ prepared according to the protocol below and using the procedure above and conventional procedures known to those skilled in the art ] N, N-dimethylformamide (10 mL) was added N, N-diisopropylethylamine (626 mg,4.84mmol,0.8mL,4 eq) followed by stirring at 80 ℃ for 16 hours. The reaction mixture was concentrated to give a residue. The residue was purified by semi-preparative reverse phase HPLC (column: phenomenex luna C, 250, 50mm, 10um; mobile phase: [ water (0.225% FA) -ACN ]; B%:10% -40%,30 min, 40% min). Dimethyl 4- [2- [2- [2- [2- [2- [3- [4- (5-methylpyrido [4,3-b ] indol-7-yl) piperazin-1-yl ] propoxy ] ethoxy ] benzene-1, 2-dicarboxylic acid ester (131 mg,0.19mmol,15% yield, 100% purity) was obtained as a brown oil.
Step 4 2- (2, 6-Dioxopiperidin-3-yl) -5- ((15- (4- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) piperazin-1-yl) -3,6,9, 12-tetraoxapentadecyl) oxy) isoindoline-1, 3-dione
Dimethyl 4- [2- [2- [2- [2- [2- [3- [4- (5-methylpyrido [4,3-b ] indol-7-yl) piperazin-1-yl ] propoxy ] ethoxy ] benzene-1, 2-dicarboxylic acid ester (120 mg,0.17mmol,1 eq.), 3-aminopiperidine-2, 6-dione (142 mg,0.86mmol,5 eq., HCl) and lithium iodide (347 mg,2.60mmol,15 eq.) are absorbed into pyridine (4 mL) in a microwave tube. The sealed tube was heated under microwaves at 120 ℃ for 2 hours. The reaction mixture was concentrated to give a residue. The residue was purified by semi-preparative reverse phase HPLC (8-38% acetonitrile +0.225% formic acid in water over 10 minutes) and then the collected fractions were concentrated to remove most of the acetonitrile and then lyophilized to give the crude product. The crude product was then purified by preparative TLC (dichloromethane/methanol=10/1), added 10mL of water and 0.2mL of 1m hydrochloric acid, and then lyophilized to give the product. 2- (2, 6-Dioxopiperidin-3-yl) -5- ((15- (4- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) piperazin-1-yl) gives-3, 6,9, 12-tetraoxapentadecyl) oxy) isoindoline-1, 3-dione dihydrochloride (20 mg,0.02mmol,14% yield) as an off-white solid.
1H NMR:(400MHz,DMSO-d6)δ:15.03(br s,1H),11.18-10.95(m,2H),9.55(s,1H),8.64(br d,J＝6.5Hz,1H),8.30(br d,J＝8.3Hz,1H),8.09(br d,J＝6.9Hz,1H),7.81(br d,J＝8.5Hz,1H),7.48-7.23(m,4H),5.11(br dd,J＝5.0,12.7Hz,1H),4.30(br s,2H),4.11(br d,J＝13.1Hz,2H),4.02(s,3H),3.78(br s,2H),3.70-3.48(m,18H),3.19(br s,3H),2.96-2.82(m,1H),2.62-2.55(m,3H),2.04(br s,3H).(M+H)+ 757.6.
Synthetic scheme for exemplary Compound 211
2- (2, 6-Dioxopiperidin-3-yl) -5- (3- (3- (3- (2- (6- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -2-azaspiro [3.3] heptane-2-yl) ethoxy) propoxy) azetidin-1-yl) isoindoline-1, 3-dione
Prepared according to the schemes below and using the procedures described above and conventional procedures known to those skilled in the art.
Synthetic schemes for exemplary Compound 212
2- (2, 6-Dioxopiperidin-3-yl) -5- (3- (2- ((4- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) but-2-yn-1-yl) oxy) ethoxy) azetidin-1-yl) isoindoline-1, 3-dione
Step 1 t-butyl 3- (2-ethoxy-2-oxo-ethoxy) azetidine-1-carboxylate
To a mixture of tert-butyl 3-hydroxyazetidine-1-carboxylate (3 g,17.32mmol,1 eq.) and rhodium diacetoxy (diacetoxyrhodium) (766 mg,1.73mmol,0.1 eq.) in dichloromethane (50 mL) was added dropwise ethyl 2-diazoacetate (11.86 g,103.92mmol,6 eq.) at 0 ℃. The reaction mixture was then stirred at 25 ℃ for 4 hours. TLC showed that starting material was not consumed. The reaction was then stirred at 25 ℃ for an additional 16 hours. To the reaction solution, acetic acid was added. The reaction was then extracted with dichloromethane (30 ml x 3) and concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=30/1 to 8:1) to give the product. Tert-butyl 3- (2-ethoxy-2-oxo-ethoxy) azetidine-1-carboxylic acid ester (2.24 g,8.64mmol,50% yield) was obtained as a pale yellow oil.
Step 2 tert-butyl 3- (2-hydroxyethoxy) azetidine-1-carboxylate
To a suspension of lithium aluminum hydride (229.51 mg,6.05mmol,0.7 eq.) in tetrahydrofuran (30 mL) was added a solution of tert-butyl 3- (2-ethoxy-2-oxo-ethoxy) azetidine-1-carboxylate (2.24 g,8.64mmol,1 eq.) in tetrahydrofuran (10 mL) at-20 ℃. The reaction mixture was stirred at 0 ℃ for 0.5 hours. To the reaction solution was added water (20 mL), and the organic layer was extracted with ethyl acetate (40 ml×3). The combined organic phases were then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=200/1 to 1:1) to give a product. Tert-butyl 3- (2-hydroxyethoxy) azetidine-1-carboxylate (8238 mg,3.81mmol,44% yield) was obtained as a pale yellow oil.
Step 3 4- [ (4-methoxyphenyl) methoxy ] but-2-yn-1-ol
To a solution of but-2-yne-1, 4-diol (5 g,58.08mmol,1 eq.) in N, N-dimethylformamide (50 mL) at 0℃was added sodium hydride (2.32 g,58.08mmol, 60% in mineral oil, 1 eq.). The mixture was stirred at 0 ℃ for 0.5 hours. Methoxybenzyl chloride (9.55 g,60.98mmol,8.3ml,1.05 eq.) was then slowly added to the mixture at 0 ℃, and the mixture was stirred at 25 ℃ for 4 hours. Water (40 mL) was added to the reaction. The solution was extracted with ethyl acetate (40 ml x 3). The combined organic phases were then washed with brine (20 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=30/1 to 3:1) to give the product. 4- [ (4-methoxyphenyl) methoxy ] but-2-yn-1-ol (2.64 g,12.80mmol,22% yield) was obtained as a pale yellow oil.
Step4 1- (4-Bromobut-2-alkynyloxymethyl) -4-methoxybenzene
To a solution of 4- [ (4-methoxyphenyl) methoxy ] but-2-yn-1-ol (1 g,4.85mmol,1 eq.) and perbromomethane (1.61 g,4.85mmol,1 eq.) in dichloromethane (10 mL) at 0 ℃ was added triphenylphosphine (1.40 g,5.33mmol,1.1 eq.). The solution was stirred at 25 ℃ for 16 hours. TLC showed complete consumption of starting material. The reaction solution was concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/0 to 80:1) to give the product. 1- (4-Bromobut-2-alkynyloxymethyl) -4-methoxy-benzene (1 g,3.72mmol,77% yield) was obtained as a pale yellow oil.
The final compound, 2- (2, 6-dioxopiperidin-3-yl) -5- (3- (2- ((4- ((1 r,3 r) -3- ((5- (5-methyl) -5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) but-2-yn-1-yl) oxy) ethoxy) azetidin-1, 3-dione, was prepared according to the scheme below, and using the procedure described above and conventional procedures known to those skilled in the art.
Synthetic scheme for exemplary Compound 213
2- (2, 6-Dioxopiperidin-3-yl) -5- (6- (2- (2- ((1 r,3 r) -3- ((5- (5-methyl-5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) cyclobutoxy) ethoxy) -2-azaspiro [3.3] heptane-2-yl) isoindoline-1, 3-dione
Prepared according to the schemes below and using the procedures described above and conventional procedures known to those skilled in the art.
Further examples are considered in the context of the present invention and are detailed below. They may be prepared as described in the accompanying schemes, or by using procedures similar to those described above (as shown).
Synthesis schemes for Compounds 215 and 217
Can be prepared according to the following schemes and using the above procedure and conventional procedures known to those skilled in the art.
Alternatively, one skilled in the art will recognize that different sequences of steps and/or different protecting groups may be used in the assembly of the linker of the examples described below. In addition, different orders of attaching the joints to the PTM and ULM may be used for different instances, and sometimes different orders of joint assembly and PTM/ULM attachment may be used interchangeably for a given instance (i.e., first attaching the PTM, then the ULM, or first attaching the ULM, then the PTM). For example, the linker of compound 216 may be assembled as shown in the schemes below.
Compound 216 may then be synthesized according to the scheme below.
Alternatively, compound 216 may be synthesized according to the schemes below, using different PTM and ULM attachment sequences.
Synthetic scheme for exemplary Compound 4
4- ((14- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione
Prepared according to the following protocol using the procedure described above and conventional procedures known to those skilled in the art.
1H NMR(400MHz,CDCl3):δ9.30(s,1H),8.90(br,1H),8.52(d,J＝5.6Hz,1H),8.42(d,J＝2,8Hz,1H),8.14(d,J＝8.0Hz,1H),7.49(dd,J＝2.4,8.8Hz,1H),7.57(s,1H),7.26-7,46(m,3H),6.97(d,J＝7.2Hz,1H),6.81-6.87(m,2H),6.35-6.46(m,1H),4.89-4.98(m,1H),4.54(t,J＝4.8Hz,2H),3.90(t,J＝4.8Hz,2H),3.61-3-74(m,15H),3.37-3.81(m,2H),2.65-2.92(m,3H),2.07-2.15(m,1H).
Using the procedure described for compound 4, the following were prepared, compound 2, compound 3 and compound 48.
Synthetic scheme for exemplary Compound 7
(2S, 4R) -1- ((S) -14- (4- (benzo [4,5] imidazo [1,2-a ] pyrimidin-2-yl) piperazin-1-yl) -2- (tert-butyl) -4-oxo-6, 9, 12-trioxa-3-aza-tetradecyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide
Prepared according to the following protocol using the procedure described above and conventional procedures known to those skilled in the art.
1H NMR(400MHz,MeOD):δ8.85(s,1H),8.71(d,J＝7.6Hz,1H),7.70(d,J＝8.0Hz,1H),7.55(d,J＝8.0Hz,1H),7.34-7.42(m,5H),7.22-7.23(m,1H),6.76(d,J＝7.6Hz,1H),4.68(s,1H),4.47-4.57(m,4H),4.30-4.39(m,1H),4.05(s,3H),3.56-4.87(m,23H),2.64(s,4H),2.45(s,3H),2.19(br,1H),2.04(br,1H),1.03(s,9H).
Using the procedure described for compound 7, the following were prepared, compound 11, compound 12, compound 15, compound 16, compound 19, compound 20, compound 23, compound 25, and compound 26.
Synthetic scheme for exemplary Compound 10
(2S, 4R) -1- ((S) -14- (4- (benzo [4,5] imidazo [1,2-a ] pyrimidin-2-yl) piperazin-1-yl) -2- (tert-butyl) -4,14 dioxo-6, 9, 12-trioxa-3-aza-tetradecyl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide
Prepared according to the following protocol using the procedure described above and conventional procedures known to those skilled in the art.
1H NMR(400MHz,MeOD):δ8.85(s,1H),8.78(d,J＝7.6Hz,1H),7.83(d,J＝7.6Hz,1H),7.57(d,J＝7.6Hz,1H),7.35–7.40(m,6H),7.23(t,J＝8.0Hz,1H),4.98–5.00(m,1H),4.67(s,1H),4.55–4.57(m,1H),4.34–4.43(m,3H),3.83–4.03(m,7H),3.72–3.74(m,16H),2.46(s,3H),2.17–2.21(m,1H),1.95–2.10(m,1H),1.31(d,J＝8.8Hz,3H),1.03(s,9H).
Additional compounds 13, 14, 17, 18, 21, 22, 24, 41, 42 were prepared using the procedure described for compound 10.
Synthetic scheme for exemplary Compound 43
(2S, 4R) -1- ((2S) -2- (tert-butyl) -15- ((2- (4- (dimethylamino) phenyl) quinolin-6-yl) oxy) -14-hydroxy-4-oxo-6, 9, 12-trioxa-3-aza-pentadecanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide
Prepared according to the following protocol using the procedure described above and conventional procedures known to those skilled in the art.
1HNMR(400MHz,CD3OD):δ1.04(s,9H),2.05-2.13(m,1H),2.21-2.23(m,1H),2.46(s,3H),3.05(s,6H),3.65-3.74(m,10H),3.79-3.90(m,2H),3.98-4.07(m,2H),4.13-4.22(m,3H),4.33-4.37(m,1H),4.50-4.62(m,3H),4.70(s,1H),6.89(d,J＝8.8Hz,2H),7.25-7.26(m,1H),7.38-7.44(m,5H),7.83(d,J＝8.8Hz,1H),7.94-7.97(m,3H),8.17(d,J＝8.8Hz,1H),8.85(s,1H).
Using the procedure described for compound 43, the following were prepared, compound 45, compound 46, compound 47.
Synthetic scheme for exemplary Compound 8
(2S, 4R) -1- ((S) -2- (tert-butyl) -15- ((2- (4- (dimethylamino) phenyl) quinolin-6-yl) oxy) -4-oxo-6, 9,12 trioxa-3-aza-pentadecanoyl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide
Prepared according to the following protocol using the procedure described above and conventional procedures known to those skilled in the art.
1HNMR(400MHz,CD3OD):δ1.01,1.03(two singles,9H),2.07-2.25(m,4H),2.45,2.47(two singles,3H),3.04(s,6H),3.65-3.71(m,10H),3.78-3.86(m,2H),4.01-4.06(m,2H),4.18-4.21(m,2H),4.32-4.36(m,1H),4.50-4.60(m,3H),4.68-4.70(m,1H),6.88(d,J＝9.2Hz,2H),7.23-7.26(m,1H),7.34-7.44(m,5H),7.82(d,J＝8.4Hz,1H),7.92-7.96(m,3H),8.16(d,J＝8.8Hz,1H),8.85,8.86(two singles,1H).
Using the procedure described for compound 8, the following were prepared, compound 9, compound 27, compound 28, compound 29, compound 30, compound 31, compound 32, compound 33, compound 34, compound 35, compound 36, compound 37, compound 38, compound 39, compound 40, compound 44.
Synthetic scheme for exemplary Compound 49
3- (4- ((14- ((5- (5H-pyrido [4,3-b ] indol-7-yl) pyridin-2-yl) oxy) -3,6,9, 12-tetraoxatetradecyl) amino) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione
Prepared according to the following protocol using the procedure described above and conventional procedures known to those skilled in the art.
1H NMR(400MHz,CD3OD):δ9.36(s,1H),8.39-8.45(m,3H),8.30(d,J＝8.0Hz,1H),8.01(dd,J＝2.4,6.4Hz,1H),7.78(s,1H),7.70(d,J＝6.0Hz,1H),7.59(d,J＝8.4Hz,1H),7.26(t,J＝7.6Hz,1H),7.03(d,J＝7.6Hz,1H),6.90(d,J＝8.8Hz,1H),6.80(d,J＝8.0Hz,1H),5.12(dd,J＝5.2,13.6Hz,1H),4.47(t,J＝4.4Hz,2H),4.27(d,J＝2.4Hz,2H),3.85(d,J＝4.4Hz,2H),3.62-3.68(m,14H),3.36(t,J＝5.6Hz,2H),2.75-2.95(m,2H),2.35-2.47(m,1H),2.10-2.21(m,1H).
Compound 218 may be prepared using a procedure similar to compound 195.
Compound 219 can be prepared using a procedure similar to that of compound 73/180/112.
Compound 220 may be prepared using a procedure similar to that of compound 73/173.
Compound 221 can be prepared using a procedure similar to that of compound 111/127.
Compound 222 can be prepared using a procedure similar to that of compound 141/180.
Compound 223 may be prepared using a procedure similar to compound 102/180.
Compounds 224 and 225 may be prepared according to the following schemes.
Using the methods described above (including the general methods of compounds 73, 173, and 180), compounds 226 through 234 can be prepared in a similar manner using conventional procedures known to those skilled in the art.
In addition, compounds 235-240 can be prepared by combining these methods with the procedures described above for compounds 138, 139, 140, and 203.
Compounds 241 to 247 can be prepared by using procedures similar to those of compounds 82/198 and 180.
Compounds 248 to 251 can be prepared based on compound 82 followed by additional linker processing in a manner similar to the methods described above and known to those skilled in the art.
Compounds 252 to 256 can be prepared based on the methods of compounds 104, 99 and 198 and combinations thereof.
Additional examples, compounds 257 through 330, may be prepared based on the basic PTM, ULM and linker methods described above, and in combination with suitable functional and protecting group processing known to those skilled in the art.
Exemplary PROTAC of the present disclosure may be prepared from the PTM embodiments of the present disclosure using the previously described methods of linker and E3 ligase binding moiety attachment.
Exemplary PROTAC of the present disclosure is represented by the structures in tables 1 and 2, while data relating to exemplary PROTAC is shown in tables 2 and 3.
Table 1. Exemplary PROTAC of the present disclosure.
* Each compound was tested at 1000nM, 300nM and 100nM as described in paragraph [1162 ]. The highest degradation observed at any dose of each compound is captured in Table 1 by A. Ltoreq.50% tau protein remaining after 72 hours of incubation with the test compound, B. Ltoreq.80% and >50% tau protein remaining after 72 hours of incubation with the test compound, C. Gt80% tau protein remaining after 72 hours of incubation with the test compound.
Table 2. Exemplary PROTAC of the present disclosure.
* Each compound was tested at 300nM, 100nM, 33nM and 11nM as described in paragraph [1162 ]. The highest degradation observed at any dose of each compound is captured in Table 2 by A. Ltoreq.50% tau protein remaining after 72 hours of incubation with the test compound, B. Ltoreq.80% and >50% tau protein remaining after 72 hours of incubation with the test compound, C. Gt80% tau protein remaining after 72 hours of incubation with the test compound.
Determination of Tau protein in vitro degradation
To determine the effect of PROTAC on tau protein degradation, SK-N-SH cells were seeded in 24-well tissue culture treated plates for at least 18 hours prior to compound addition. After incubation with tau PROTAC at 1000nM, 300nM and 100nM for Table 1 and 300nM, 100nM, 33nM and 11nM for Table 2 for 72 hours, tau PROTAC was evaluated for tau degradation by lysis of cells with protease inhibitors in lysis buffer. Cell lysates were electrophoresed on standard SDS-PAGE gels and Tau levels were detected by western blotting using Tau-13 antibodies from Abcam (Cambridge, UK) which bind all forms of human Tau. The highest degradation observed at any dose of each compound is shown in tables 1 and 2 above.
In vivo degradation of Tau protein
In the study, 21 male BI6 wild type mice were divided into seven groups of three mice and subjected to a single treatment via bilateral intrahippocampal injection vehicle ECP-1 (groups [ 5% EtOH in pH 7.4 phosphate buffer and 5%Cremophore RH40]; group A; see FIG. 1) or Compound 4tau PROTAC (3. Mu.L of 1mg/mL ECP-1 solution ]; groups B to G; see FIG. 1). As shown in fig. 1, all animals were sacrificed at some time point after the test item or vehicle injection and brain samples were collected. The hippocampus was excised and total tau levels were measured with Meso Scale Discovery assay kit. The results are presented in figure 1.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
One aspect of the present disclosure provides a difunctional compound having the chemical structure:
ULM―L―PTM,
or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or prodrug thereof,
Wherein:
the ULM is a small molecule E3 ubiquitin ligase binding moiety that binds to E3 ubiquitin ligase;
The PTM is a Tau protein targeting moiety, and
The L is a bond or a chemical linking moiety linking ULM and PTM.
In any aspect or embodiment described herein, the E3 ubiquitin ligase binding moiety targets an E3 ubiquitin ligase selected from Von Hippel-Lindau (VLM) and Cereblon (CLM).
In any aspect or embodiment described herein, the PTM is represented by formula I, II, III, IV, V, VI, VII, VIII, IX, X or XI:
wherein:
A. b, C, D, E and F are independently selected from optionally substituted 5 or 6 membered aryl or heteroaryl rings, optionally substituted 4 to 7 membered cycloalkyl or heterocycloalkyl, wherein contact between the circles indicates ring fusion, and
L PTM is selected from a bond, alkyl, alkenyl or alkynyl, optionally interrupted by one or more rings (i.e. cycloalkyl, heterocycloalkyl, aryl or heteroaryl), or one or more functional groups selected from-O-, -S-, -NR 1 PTM - (wherein R 1 PTM is selected from H or alkyl), -n=n-, -S (O) -, -SO 2-、-C(O)-、-NHC(O)-、-C(O)NH-、-NHSO2 -, -NHC (O) NH-, -NHC (O) O-, or-OC (O) NH-, wherein the functional groups are optionally located at either end of the linker.
In any aspect or embodiment described herein, at least one of A, B, C, F or a combination thereof is selected from an optionally substituted 5 or 6 membered aryl or heteroaryl ring.
In any aspect or embodiment described herein, the rings of A, B, C, D and E (e.g., aryl and heteroaryl rings) of PTM are optionally substituted with 18 substituents each independently selected from the group consisting of alkyl, alkenyl, haloalkyl, halogen, hydroxy, alkoxy, fluoroalkoxy, amino, alkylamino, dialkylamino, amido, trifluoromethyl and cyano, wherein the alkyl and alkenyl are further optionally substituted.
In any aspect or embodiment described herein, the PTM is formula I, and:
A. the B and C rings are independently 5 or 6 membered fused aryl or heteroaryl rings;
l PTM is selected from a bond or alkyl, and
D is selected from 6-membered aryl, heteroaryl or heterocycloalkyl,
Wherein A, B, C and D are optionally substituted with alkyl, haloalkyl, halogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, trifluoromethyl or cyano.
In any aspect or embodiment described herein, the PTM is formula I, and:
a and C are phenyl or 6 membered heteroaryl rings;
b is a 5 membered heteroaryl ring;
l PTM is a bond, and
D is a 6 membered heteroaryl or 6 membered heterocycloalkyl ring,
Wherein each A, B, C and D is optionally independently substituted with alkyl, haloalkyl, halogen, hydroxy, alkoxy, amino, dialkylamino, trifluoromethyl, or cyano, and wherein the nitrogen atom of any one of the A, B, C and D rings is not directly attached to a heteroatom or carbon atom to which the other heteroatom is directly attached.
In any aspect or embodiment described herein, the PTM is of formula III or IV, and:
A. B and C are 5 or 6 membered fused aryl or heteroaryl rings;
l PTM is selected from a bond or alkyl, and
D and E are 5 or 6 membered fused aryl or heteroaryl rings;
Wherein A, B, C, D and E are optionally substituted with alkyl, haloalkyl, halogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, trifluoromethyl or cyano.
In any aspect or embodiment described herein, the PTM is represented by a chemical structure selected from the group consisting of:
wherein:
R 1、R2 and R 3 are independently selected from H, methyl, ethyl, 2-fluoroethyl and 2, 2-trifluoroethyl;
R 4 and R 5 are independently selected from H, methyl, ethyl and halogen, and
R 6 is 1 to 2 substituents independently selected from H, methyl, ethyl and halogen.
In any aspect or embodiment described herein, the PTM is represented by a chemical structure selected from the group consisting of:
wherein:
r 1、R2 and R 3 are independently selected from H, optionally substituted alkyl, methyl, ethyl, 2-fluoroethyl and 2, 2-trifluoroethyl, and
R 7、R8、R9 and R 10 are independently selected from 1 to 8 substituents of H, optionally substituted alkyl, haloalkyl, halogen, hydroxy, alkoxy, amino, dialkylamino, acetamido, trifluoromethyl or cyano.
In any aspect or embodiment described herein, the PTM is represented by a chemical structure selected from the group consisting of:
In any aspect or embodiment described herein, the ULM is a Von Hippel-Lindau (VHL) ligase binding moiety (VLM) represented by the following structure:
wherein:
Each X 1、X2 is independently selected from the group consisting of a bond, O, NR Y3、CRY3RY4, c= O, C =s, SO, and SO 2;
each R Y3、RY4 is independently selected from H, linear or branched C 1-6 alkyl optionally substituted with 1 or more halogens, C 1-6 alkoxy);
r P is 1,2, or 3 groups, each independently selected from H, halogen, -OH, C 1-3 alkyl;
W 3 is selected from optionally substituted-T-N (R 1aR1b), optionally substituted-T-N (R 1aR1b)X3, -T-aryl, optionally substituted-T-heteroaryl, optionally substituted-T-heterocycle, optionally substituted-NR 1 -T-aryl, optionally substituted-NR 1 -T-heteroaryl or optionally substituted-NR 1 -T-heterocycle;
x 3 is c= O, R 1、R1a、R1b;
R 1、R1a、R1b are each independently selected from H, linear or branched C 1-C6 alkyl 、RY3C＝O、RY3C＝S、RY3SO、RY3SO2、N(RY3RY4)C＝O、N(RY3RY4)C＝S、N(RY3RY4)SO optionally substituted with 1 or more halogen or-OH groups, and N (R Y3RY4)SO2;
T is selected from optionally substituted alkyl, - (CH 2)n -group wherein each of the methylene groups is optionally substituted with one or two substituents selected from halogen, methyl, linear or branched C 1-C6 alkyl optionally substituted with 1 or more halogen or-OH groups, or optionally substituted amino acid side chains;
n is 0 to 6;
W 4 is
R 14a、R14b, each independently selected from H, haloalkyl or optionally substituted alkyl;
W 5 is selected from phenyl or 5-10 membered heteroaryl, and
R 15 is selected from H, optionally substituted alkyl of halogen 、CN、OH、NO2、N R14aR14b、OR14a、CONR14aR14b、NR14aCOR14b、SO2NR14aR14b、NR14a SO2R14b、, optionally substituted haloalkyl, optionally substituted haloalkoxy, aryl, heteroaryl, cycloalkyl or cycloheteroalkyl,
Wherein the dashed line indicates the attachment site of at least one PTM, another ULM (ULM '), or a chemical linker moiety coupling at least one PTM or ULM', or both, to the ULM.
In any aspect or embodiment described herein, the ULM is a Von Hippel-Lindau (VHL) ligase binding moiety (VLM) represented by the following structure:
wherein:
W 3 is selected from optionally substituted aryl, optionally substituted heteroaryl, or
R 9 and R 10 are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl, or R 9、R10 and the carbon atom to which they are attached form optionally substituted cycloalkyl;
r 11 is selected from optionally substituted heterocycle, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl,
R 12 is selected from H or optionally substituted alkyl;
R 13 is selected from H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl) alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl) carbonyl or optionally substituted aralkyl;
r 14a、R14b, each independently selected from H, haloalkyl or optionally substituted alkyl;
W 5 is selected from phenyl or 5-10 membered heteroaryl;
R 15 is selected from H, optionally substituted alkyl of halogen 、CN、OH、NO2、N R14aR14b、OR14a、CONR14aR14b、NR14aCOR14b、SO2NR14aR14b、NR14a SO2R14b、, optionally substituted haloalkyl, optionally substituted haloalkoxy, aryl, heteroaryl, cycloalkyl or cycloheteroalkyl (each independently optionally substituted);
R 16 is independently selected from H, halogen, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or optionally substituted haloalkoxy;
o is 0,1, 2, 3 or 4;
R 18 is independently selected from halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy, or linker, and
P is 0, 1, 2, 3 or 4, and wherein the dashed line indicates the attachment site of at least one PTM, another ULM (ULM '), or a chemical linker moiety coupling at least one PTM or ULM', or both, to the ULM.
In any aspect or embodiment described herein, the ULM has a chemical structure selected from the group consisting of:
wherein:
R 1 is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
R 14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl or cyclopropyl;
R 15 is selected from H, halogen, CN, OH, NO 2, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, cycloalkyl or cycloheteroalkyl;
X is C, CH 2 or C=O, and
R 3 is a bond or an optionally substituted 5 or 6 membered heteroaryl,
Wherein the dashed line indicates the attachment site of at least one PTM, another ULM (ULM '), or a chemical linker moiety coupling at least one PTM or ULM', or both, to the ULM.
In any aspect or embodiment described herein, the ULM comprises a group according to the chemical structure:
wherein:
R 14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl or cyclopropyl;
R 9 is H;
r 10 is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
r 11 is
Or optionally substituted heteroaryl;
p is 0,1, 2, 3 or 4;
each R 18 is independently halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy, or linker;
R 12 is H, C =o;
r 13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl) alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl) carbonyl or optionally substituted aralkyl, and
R 15 is selected from H, halogen, cl, CN, OH, NO 2, optionally substituted heteroaryl, optionally substituted aryl;
Wherein the dashed line indicates the attachment site of at least one PTM, another ULM (ULM '), or a chemical linker moiety coupling at least one PTM or ULM', or both, to the ULM.
In any aspect or embodiment described herein, the ULM comprises a group selected from the following structures:
Wherein the benzene rings in ULM-a1 to ULM-a15, ULM-b1 to ULM-b12, ULM-c1 to ULM-c15 and ULM-d1 to ULM-d9 are optionally substituted with fluorine, lower alkyl and alkoxy groups, and wherein the dashed lines indicate the attachment sites of at least one PTM, another ULM (ULM ') or a chemical linker moiety coupling at least one PTM or ULM' or both with ULM-a.
In any aspect or embodiment described herein, the ULM is a cereblon ligase binding moiety (CLM) that is thalidomide, lenalidomide, pomalidomide, analogs thereof, isosteres thereof, or derivatives thereof.
In any aspect or embodiment described herein, the CLM has a chemical structure represented by:
wherein:
W is selected from CH 2、CHR、C＝O、SO2, NH, and N-alkyl;
each X is independently selected from O, S and H 2;
Y is selected from CH 2, -C=CR', NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O, and S;
z is selected from O, S and H 2;
g and G 'are independently selected from H, alkyl (straight chain, branched, optionally substituted with R'), OH, R 'OCOOR, R' OCONRR, CH 2 -heterocyclyl optionally substituted with R ', and benzyl optionally substituted with R';
Q 1、Q2、Q3 and Q 4 represent carbon C substituted with a group independently selected from R', N or N-oxide;
a is independently selected from H, alkyl, cycloalkyl, cl and F;
R comprises: -CONR 'R ", -OR', -NR 'R", -SR', -SO 2R'、-SO2 NR 'R ", -CR' R" -, -CR 'NR' R "-, -aryl, -heteroaryl, -alkyl (straight, branched, optionally substituted), -cycloalkyl, -heterocyclyl 、-P(O)(OR')R"、-P(O)R'R"、-OP(O)(OR')R"、-OP(O)R'R"、-Cl、-F、-Br、-I、-CF3、-CN、-NR'SO2NR'R"、-NR'CONR'R",-CONR'COR"、NR'C(＝N-CN)NR'R"、-C(＝N-CN)NR'R"、-NR'C(＝N-CN)R"、-NR'C(＝C-NO2)NR'R"、-SO2NR'COR"、-NO2、-CO2R'、-C(C＝N-OR')R"、-CR'＝CR'R"、-CCR'、-S(C＝O)(C＝N-R')R"、-SF5, OR-OCF 3;
r' and R "are independently selected from a bond, H, N, N-oxide, alkyl (straight, branched), cycloalkyl, aryl, heteroaryl, heterocycle, -C (=o) R, or heterocyclyl, each of which is optionally substituted;
represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific, and
R n contains a functional group or atom,
Wherein n is an integer from 1 to 4, and wherein
When n is 1, R n is modified to be covalently linked to the linker group (L), and
When n is 2,3 or 4, then one R n is modified to covalently attach to the linker group (L), and optionally any other R n is modified to covalently attach to PTM, CLM, a second CLM having the same chemical structure as CLM, CLM', a second linker, or any multiple or combination thereof.
In any aspect or embodiment described herein, the CLM has a chemical structure represented by:
wherein:
w is independently selected from CH2, c= O, NH and N-alkyl;
r is independently selected from H, methyl, alkyl;
represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific, and
Rn comprises 1-4 independently selected functional groups or atoms, and optionally one of them is modified to be covalently linked to a PTM, chemical linker group (L), CLM (or CLM'), or a combination thereof.
In any aspect or embodiment described herein, the CLM has a chemical structure represented by:
Wherein the dashed lines indicate joint attachment points.
In any aspect or embodiment described herein, the linker (L) comprises a chemical structural unit represented by the formula:
-(A)q-,
wherein:
a is a group attached to the ULM or PTM moiety, and
Q is an integer greater than or equal to 1,
Wherein A is selected from C 3-11 cycloalkyl optionally substituted with 0-6R L1 and/or R L2 groups, C 3-11 heterocyclyl optionally substituted with 0-6R L1 and/or R L2 groups, aryl optionally substituted with 0-6R L1 and/or R L2 groups, heteroaryl optionally substituted with 0-6R L1 and/or R L2 groups, wherein R L1 or R L2 are each independently optionally linked to other groups to form cycloalkyl and/or heterocyclyl moieties optionally substituted with 0-4R L5 groups;
R L1、RL2、RL3、RL4 and R L5 are each independently H, halogen, C 1-8 alkyl, OC 1-8 alkyl, SC 1-8 alkyl, NHC 1-8 alkyl, N (C 1-8 alkyl) 2、C3-11 cycloalkyl, aryl, heteroaryl, C 3-11 heterocyclyl, OC 1-8 cycloalkyl, SC 1-8 cycloalkyl, NHC 1-8 cycloalkyl, N (C 1-8 cycloalkyl) 2、N(C1-8 cycloalkyl) (C 1-8 alkyl), OH, NH 2、SH、SO2C1-8 alkyl, P (O) (OC 1-8 alkyl) (C 1-8 alkyl), P (O) (OC 1-8 alkyl) 2、CC-C1-8 alkyl, CCH, ch=ch (C 1-8 alkyl), C (C 1-8 alkyl) =ch (C 1-8 alkyl), c (C 1-8 alkyl) =c (C 1-8 alkyl) 2、Si(OH)3、Si(C1-8 alkyl) 3、Si(OH)(C1-8 alkyl) 2、COC1-8 alkyl, CO 2 H, halogen, CN, CF 3、CHF2、CH2F、NO2、SF5、SO2NHC1-8 alkyl, SO 2N(C1-8 alkyl) 2、SONHC1-8 alkyl, SON (C 1-8 alkyl) 2、CONHC1-8 alkyl, CON (C 1-8 alkyl) 2、N(C1-8 alkyl) CONH (C 1-8 alkyl), N (C 1-8 alkyl) CON (C 1-8 alkyl) 2、NHCONH(C1-8 alkyl), NHCON (C 1-8 alkyl) 2、NHCONH2、N(C1-8 alkyl) SO 2NH(C1-8 alkyl), N (C 1-8 alkyl) SO 2N(C1-8 alkyl) 2、NH SO2NH(C1-8 alkyl, NH SO 2N(C1-8 alkyl) 2、NH SO2NH2.
In any aspect or embodiment described herein, the linker (L) comprises a group represented by a general structure selected from the group consisting of:
-N(R)-(CH2)m-O(CH2)n-O(CH2)o-O(CH2)p-O(CH2)q-O(CH2)r-OCH2-,
-O-(CH2)m-O(CH2)n-O(CH2)o-O(CH2)p-O(CH2)q-O(CH2)r-OCH2-,
-O-(CH2)m-O(CH2)n-O(CH2)o-O(CH2)p-O(CH2)q-O(CH2)r-O-;
-N(R)-(CH2)m-O(CH2)n-O(CH2)o-O(CH2)p-O(CH2)q-O(CH2)r-O-;
-(CH2)m-O(CH2)n-O(CH2)o-O(CH2)p-O(CH2)q-O(CH2)r-O-;
-(CH2)m-O(CH2)n-O(CH2)o-O(CH2)p-O(CH2)q-O(CH2)r-OCH2-;
Wherein each m, N, O, p, q and R is independently 0, 1, 2, 3, 4, 5, 6, provided that when the number is zero, no N-O or O-O bond is present, R is selected from H, methyl or ethyl, and X is selected from H or F;
in any aspect or embodiment described herein, the linker (L) is selected from:
in any aspect or embodiment described herein, the linker (L) is selected from:
Wherein each n and m is independently 0, 1, 2, 3, 4, 5 or 6.
In any aspect or embodiment described herein, L comprises the following chemical structure:
wherein:
W L1 and W L2 are each independently a 4-8 membered ring having 0-4 heteroatoms, optionally substituted with RQ, each RQ is independently H, halogen, OH, CN, CF3, C1-C6 alkyl (straight, branched, optionally substituted), C1-C6 alkoxy (straight, branched, optionally substituted), or 2 RQ groups together with the atoms to which they are attached form a 4-8 membered ring system containing 0-4 heteroatoms;
Y L1 is each independently a bond, C1-C6 alkyl (straight, branched, optionally substituted) and optionally one or more C atoms are replaced by O, or C1-C6 alkoxy (straight, branched, optionally substituted), and
The dashed lines indicate the attachment points to the PTM or ULM portions.
In any aspect or embodiment described herein, L comprises the following chemical structure:
wherein:
W L1 and W L2 are each independently aryl, heteroaryl, cyclyl, heterocyclyl, C 1-6 alkyl, bicyclo, biaryl, or biaheterocyclyl, each optionally substituted with R Q, each R Q is independently H, halogen, OH, CN, CF 3, hydroxy, nitro, C≡CH, C 2-6 alkenyl, C 2-6 alkynyl, C 1-C6 alkyl (straight, branched, optionally substituted), C 1-C6 alkoxy (straight, branched, optionally substituted), OC 1-3 alkyl (optionally substituted with 1 or more-F), OH, NH 2、NRY1RY2, CN, or 2R Q groups together with the atoms to which they are attached form a 4-8 membered ring system containing 0-4 heteroatoms;
Y L1 are each independently a bond, NR YL1、O、S、NRYL2、CRYL1RYL2、C＝O、C＝S、SO、SO2、C1-C6 alkyl (linear, branched, optionally substituted), and optionally one or more C atoms replaced by O;
Q L is a 3-6 membered cycloaliphatic or aromatic ring having 0-4 heteroatoms, optionally bridged, optionally substituted with 0-6R Q, each R Q is independently H, C 1-6 alkyl (straight chain, branched, optionally substituted with 1 or more halogens, C 1-6 alkoxy), or 2R Q groups together with the atoms to which they are attached form a 3-8 membered ring system containing 0-2 heteroatoms);
R YL1、RYL2 is each independently H, OH, C 1-6 alkyl (straight chain, branched, optionally substituted with 1 or more halogens, C 1-6 alkoxy), or R 1、R2, together with the atoms to which they are attached, forms a 3-8 membered ring system containing 0-2 heteroatoms;
n is 0 to 10, and
The dashed lines indicate the attachment points to the PTM or ULM portions.
In any aspect or embodiment described herein, L is a polyethyleneoxy group comprising 1 to 10 ethylene glycol units, optionally substituted with aryl or phenyl.
In any aspect or embodiment described herein, the compound comprises a plurality of ULMs, a plurality of PTMs, a plurality of linkers, or any combination thereof.
In any aspect or embodiment described herein, the compound is selected from compounds 1-330 (table 1 or table 2).
In any aspect or embodiment described herein, the compound is selected from table 1 or table 2 (i.e., compounds 1-330).
In any aspect or embodiment described herein, the compound has a chemical structure selected from formulas CI through CV:
wherein:
R 101 is 1-2 substituents independently selected from H, alkyl, halo, haloalkyl or cyano;
R 102 is selected from H, alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl;
r 103 is 1-2 substituents independently selected from H, alkyl, halo, haloalkyl or cyano;
R 104 is 1-2 substituents independently selected from H, alkyl, halo, haloalkyl or cyano;
r 105 is 1-2 substituents independently selected from H, alkyl, halo, haloalkyl or cyano;
R106、R107、R109、R110、R111、R112、R113、R114、R116、R117、R120、R121、R126、R127、R122 And R 123 are each independently selected from H, alkyl, halo, or haloalkyl;
R 108 is 1-2 substituents independently selected from H, alkyl, halo, haloalkyl, cyano or methoxy;
r 115 is selected from H, alkyl, and haloalkyl;
r 118 and R 119 are independently selected from H, alkyl, halogen or haloalkyl, or R 118 and R 119 together with the carbon atom to which they are attached represent a 3-6 membered cycloalkyl or heterocycloalkyl ring, for example cyclopropane or oxetane;
R 124 and R 125 are independently selected from H, alkyl, halogen or haloalkyl, or R 124 and R 125 together with the carbon atom to which they are attached represent a 3-6 membered cycloalkyl or heterocycloalkyl ring, for example cyclopropane or oxetane;
g is phenyl or a 5-or 6-membered heteroaryl ring, and
Z is CH 2 or c=o.
A further aspect of the present disclosure provides a composition comprising an effective amount of a bifunctional compound of the present disclosure and a pharmaceutically acceptable carrier.
In any aspect or embodiment described herein, the composition further comprises at least one of an additional bioactive agent, another difunctional compound, or a combination thereof.
In any aspect or embodiment described herein, the additional bioactive agent is an anti-neurodegenerative agent.
In any aspect or embodiment described herein, the additional bioactive agent is a P-gp inhibitor.
In any aspect or embodiment described herein, the P-gp inhibitor is amiodarone, azithromycin, captopril, clarithromycin, cyclosporin, piperine, quercetin, quinidine, quinine, reserpine, ritonavir, taroquinol, irinotecan, or verapamil.
Another aspect of the present disclosure provides a composition comprising a pharmaceutically acceptable carrier and an effective amount of at least one compound of the present disclosure for use in treating a disease or disorder in a subject, the method comprising administering the composition to a subject in need thereof, wherein the compound is effective to treat or ameliorate at least one symptom of the disease or disorder.
In any aspect or embodiment described herein, the disease or disorder is associated with Tau accumulation and aggregation.
In any aspect or embodiment described herein, the disease or disorder is a neurodegenerative disease associated with Tau accumulation and aggregation.
In any aspect or embodiment described herein, the disease or condition is acquired epileptiform aphasia, acute disseminated encephalomyelitis, ADHD, idedi's pupil, idedi's syndrome, adrenoleukodystrophy, callus dysplasia, agnosia, eikadi's syndrome, AIDS-neurological complications, alexander disease, alper's disease, alternant hemiplegia, alzheimer's disease, amyotrophic lateral sclerosis, brain-free deformity, aneurysms, angel's syndrome, hemangiomatosis, hypoxia, aphasia, apraxia, arachnoid cyst, arachnoiditis, alzhi, arteriovenous deformity, albert syndrome, Ataxia, telangiectasia, ataxia and cerebellar/spinal cerebellar degeneration, attention deficit hyperactivity disorder, autism, autonomic dysfunction, back pain, papanicolaou syndrome, barter's disease, beckmann's muscle rigidity, behcet's disease, bell palsy, benign essential blepharospasm, benign focal muscular atrophy, benign intracranial hypertension, bo-Luo Ershi syndrome, bischwann disease, blepharospasm, bu-Su Ershi syndrome, brachial plexus injury, bradbury-Eggeleston syndrome, brain and spinal tumors, cerebral aneurysms, brain injury, brown-Szechter syndrome, bulbar muscular atrophy, Kanwana disease, carpal tunnel syndrome causalgia, spongiform tumor, spongiform hemangioma, spongiform vascular malformation, central cervical syndrome, central chordae syndrome, central pain syndrome, cranial disorder, cerebellar degeneration, cerebellar hypoplasia, cerebral aneurysm, cerebral arteriosclerosis, brain atrophy, cerebral beriberi, cerebral giant salacia, cerebral hypoxia, cerebral paralysis, brain-eye-face-bone syndrome, charpy-March disease, chiari deformity, chorea acanthocytosis, chronic Inflammatory Demyelinating Polyneuropathy (CIDP), chronic erectile intolerance, chronic pain type II cocaine syndrome, ke-le two syndrome, COFS, cavitary brain, coma and persistent plant states, complex regional pain syndrome, congenital facial paralysis, congenital muscle weakness, congenital myopathy, congenital spongiform vessels, deformity, corticobasal degeneration, craniarteritis, craniosynostosis, creutzfeldt-jakob disease, cumulative trauma disorder, cushing's syndrome, giant cell inclusion body disease, cytomegalovirus infection, chorea of the eye, dan-Wo Ershi syndrome, morse, demuxia syndrome, deep brain stimulation of parkinson's disease, dejerine-Klumpke paralysis, dementia-multiple cerebral infarctions, dementia-semanticance, dementia-subcortical, subcortical pain, Dementia with lewy bodies, dentate nucleus cerebellar ataxia, dentate nucleus erythronuclear atrophy, dermatomyositis, developmental dyskinesia, devickers syndrome, diabetic neuropathy, diffuse sclerosis, familial autonomic nerve abnormalities, dyskinesia, cerebellar dyssynergia, myoclonus, progressive cerebellar dyssynergia, dystonia, early stage infant epilepsy, encephalopathy, jetlag syndrome, comatose encephalitis, brain swelling, encephalopathy, cerebral trigeminal angiomatosis, epilepsy, erb-Duchenne and Dejerine-Klumpke paralysis, european-Behcet's paralysis, fabry's disease, French syndrome, syncope, familial autonomic dysfunction, familial hemangioma, familial idiopathic basal ganglia calcification, familial periodic paralysis, familial spastic paralysis, febrile convulsion, fisher syndrome, sonchus infant syndrome, friedel-crafts ataxia, frontotemporal dementia, gaucher's disease, gettman syndrome, gekko Shi Xiesan disease, giant cell arteritis, giant cell inclusion body disease, leukodystrophy, glossopharyngalgia, geobanches syndrome, hash's disease, head injury, headache, persistent migraine, hemifacial spasm, hemiplegia Alterans, hereditary neuropathy, Hereditary spastic paraplegia, hereditary ataxia polyneuritis, shingles, ping Shan syndrome, hodgher's syndrome, forebrain crazy deformity, HTLV-1 related myelopathy, huntington's disease, water retention cerebral deformity, hydrocephalus-normal pressure, hydrocephalus, hyperkinesia, hypercortisolism, hypersomnia, hypotonia-infant, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, pigment incontinence, hypotonia of infant, infantile nerve axonal dystrophy, infant phytanic acid storage disease, infant Lei Fusu m disease, infantile cramps, inflammatory myopathy, Occipital split cerebral dew deformity, intestinal lipodystrophy, intracranial cysts, intracranial hypertension, isaacs syndrome, zhu Bate syndrome, kennel-Sachs syndrome, kennedy's disease, kingbriner's syndrome, kernel-Living syndrome, kernel-Fei Ershi syndrome, kernel-Techner's syndrome (KTS), kernel-Buddy's syndrome, kosakoff forgetting syndrome, kerabe disease, cookawer's disease, kuru, landau-Airy's muscle weakness syndrome, landau-Klefner syndrome, lateral femoral, cutaneous nerve entrapment, bulbar lateral syndrome, learning disorders, lei's disease, lei-Goos syndrome, lei-Nardy's syndrome, Leukodystrophy, levine-CRITCHLEY syndrome, lewy body dementia, lipid storage disorder, cerebral palsy, atresia syndrome, gray's disease, lupus-neurology, sequelae, lyme disease-neurological complications, equine-Johnson's disease, megabrain, mania, megabrain, michelia-Luo Ershi syndrome, meningitis and encephalitis, mentha's disease, paresthesia femoral pain, metachromatic, leukodystrophy, microcephaly, migraine, millefre's syndrome, small stroke, mitochondrial myopathy, morbites syndrome, single limb atrophy, motor neuron disease, smogopathy, mucolipidosis, Mucopolysaccharidoses, multifocal motor neuropathy, multi-infarct dementia, multiple sclerosis, multiple system atrophy with orthostatic hypotension, muscular dystrophy, muscle weakness-congenital, myasthenia gravis, demyelinating diffuse sclerosis, infant myoclonus encephalopathy, myoclonus, myopathy-congenital, myopathy-thyrotoxicosis, myotonia, congenital myotonia, narcolepsy, acanthocytosis, neurodegenerative disorders with brain iron deposition, neurofibromatosis, nerve blocker malignancy, neurological complications of AIDS, neurological complications of lyme disease, neurological consequences of cytomegalovirus infection, Neurological manifestations of pompe disease, neurological sequelae of lupus, neuromyelitis optica, neuromyotonia, neuronal ceroid, lipofuscinosis, neuronal migration disorders, neuropathy-hereditary, neurosarcoidosis, neurotoxicity, moles cavernosum, niemann-pick disease, normal pressure hydrocephalus, occipital neuralgia, obesity, recessive spinal neural tube insufficiency sequences, dada syndrome, olivopontocerebellar atrophy, strabismus-clonus myoclonus, orthostatic hypotension, O' Sullivan-McLeod syndrome, overuse syndrome, pain-chronic, pain, pantothenate kinase-related neurodegeneration, Paraneoplastic syndrome, paresthesia, parkinson's disease, paroxysmal chorea athetosis, paroxysmal migraine, parry-Romberg, pet-Mei-two's disease, pena Shokeir II syndrome, nerve bundle cyst, periodic paralysis, peripheral neuropathy, periventricular leukomalacia, persistent plant status, pervasive developmental disorder, phytanic acid storage disease, pick's disease, neuromarking, piriform muscle syndrome, pituitary tumor, polymyositis, pompe disease, pornoglos, postherpetic neuralgia, post-infection encephalomyelitis, post-poliomyelitis syndrome, orthostatic hypotension, Tachycardia syndrome, postural tachycardia syndrome, primary Dentatum atrophy, primary lateral sclerosis, primary progressive aphasia, prion diseases, progressive hemifacial atrophy, progressive motor ataxia, progressive multifocal, leukoencephalopathy, progressive sclerosing gray matter dystrophy, progressive supranuclear, paralysis, face-unknown, pseudoencephaloma, lambdazin hunter syndrome I (previously known), lambdazin hunter syndrome II (previously known), rasmussen encephalitis, reflex sympathetic dystrophy syndrome, lei Fusu m disease, lei Fusu m disease-infancy, repetitive movement disorder, Repetitive stress injury, restless leg syndrome, retrovirus-associated spinal cord disease, rate's syndrome, rayleigh-Dai Ershi syndrome, sacral nerve root cyst, saint Vitex's chorea, salivary gland disease, mordeHough's disease, shebrew's disease, cerebral fissure, saint Begonia disease, epilepsy, semantic dementia, dysplasia of the visual-septa type, infant swing syndrome, SHINGLES SHY-Drager syndrome, sjogren's syndrome, sleep apnea, comatose, sotos syndrome, spasticity, spinal column fissure, spinal infarction, spinal cord injury, spinal cord tumor, spinal muscular atrophy, spinal cerebellar atrophy, Spinocerebellar, degenerative, sri-Otts syndrome, stiff person syndrome, striatal degeneration, stroke, sri-Weber syndrome, subacute sclerotic encephalitis, subcortical arteriosclerotic encephalopathy, SUNCT headache dysphagia, west Duham chorea, syncope, syphilitic myelosclerosis, syringohol's disease, systemic lupus erythematosus, phthisis tardive dyskinesia, tarlov cyst, tarlov-Satwo's disease, temporal arteritis, spinal cord embolic syndrome, thomsen's myotonic, chest outlet syndrome, thyrotoxicosis, trigeminal neuralgia, todder paralysis, tourette syndrome, transient ischemic attacks, transmissible spongiform encephalopathy, transverse myelitis, traumatic brain injury, tremor, trigeminal neuralgia, tropical spastic lower limb paralysis, nodular sclerosis, vascular erectile tumors, vasculitis including temporal arteritis, embopogon disease, hill-Lin's disease (VHL), feng Leike Lin Huozeng's disease, walen Bei Geshi syndrome, wer-Huo Ershi disease, west syndrome, whiplash syndrome, hupler's disease, williams syndrome, wilson's disease, X-linked spinal bulbar atrophy or Zellweger syndrome.
In any aspect or embodiment described herein, the disease or condition is a neurological condition that accompanies at least one of huntington's disease, muscular dystrophy, parkinson's disease, alzheimer's disease, babbitt, spinal and brain injuries, epilepsy, brain tumors, meningitis, autoimmune diseases such as multiple sclerosis, neurofibromatosis, depression, amyotrophic lateral sclerosis, arteriovenous malformations, cerebral aneurysms, dural arteriovenous fistulae, headaches, memory disorders, peripheral neuropathy, post-herpetic neuralgia, spinal tumors, and stroke.
In any aspect or embodiment described herein, the disease or disorder is alzheimer's disease.

Claims (17)

1. A compound having the chemical structure:
ULM―L―PTM,
or a pharmaceutically acceptable salt thereof,
Wherein:
(a) The L is selected from:
-O-(CH2)m-O(CH2)n-O(CH2)o-O(CH2)p-O(CH2)q-O(CH2)r-O-;
-(CH2)m-O(CH2)n-O(CH2)o-O(CH2)p-O(CH2)q-O(CH2)r-O-;
wherein:
Each m, N, O, p, q and r of L is independently 0, 1,2,3, 4, 5, or 6, provided that when either of m, N, O, p, q and r is zero, no N-O or O-O bond is formed,
And
Wherein each n and m is independently 0, 1,2,3,4, 5 or 6;
(b) The ULM is:
wherein:
W is CH 2 or c=o;
Each X is O;
Z is O;
g is H;
q 1、Q2 and Q 4 are each independently CH or CR;
Q 3 is N, CH or CR;
A is H;
n is 1, 2,3 or 4;
R is-OR', C 1-6 alkyl, -Cl, -F, -Br OR-I, wherein one R is covalently linked to L;
R' is H, and
Representing a bond that is stereospecific or non-stereospecific, and
(C) The PTM is selected from:
wherein:
R 1 is selected from H and C 1-6 alkyl optionally substituted by 1, 2or 3 halogens, and
R 7、R8 and R 9 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, halogen, hydroxy, C 1-6 alkoxy, and cyano.
2. The compound of claim 1, wherein R 1 is selected from methyl, ethyl, 2-fluoroethyl, and 2, 2-trifluoroethyl.
3. The compound according to claim 1, wherein the PTM is selected from the group consisting of:
4. the compound of claim 1, wherein the ULM is:
wherein:
W is selected from CH 2 and c=o;
A is H, and Representing a bond that is stereospecific or non-stereospecific.
5. The compound of claim 1, wherein the ULM is:
Wherein the method comprises the steps of Indicating the point of attachment of L.
6. A compound, wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
8. The pharmaceutical composition of claim 7, wherein the composition further comprises at least one additional bioactive agent.
9. The pharmaceutical composition of claim 8, wherein the additional bioactive agent is an anti-neurodegenerative agent.
10. The pharmaceutical composition of claim 8, wherein the additional bioactive agent is a P-gp inhibitor.
11. The pharmaceutical composition of claim 10, wherein the P-gp inhibitor is amiodarone, azithromycin, captopril, clarithromycin, cyclosporin, piperine, quercetin, quinidine, quinine, reserpine, ritonavir, tarquetiapine, iridamide, or verapamil.
12. Use of a compound according to claim 1 or a pharmaceutical composition according to claim 7 in the manufacture of a medicament for the treatment of a Tau-associated disease or disorder.
13. The use of claim 12, wherein the Tau-associated disease or disorder is a neurological disorder selected from huntington's disease, muscular dystrophy, parkinson's disease, alzheimer's disease, barbites, spinal cord and brain injury, epilepsy, brain tumors, meningitis, multiple sclerosis, neurofibromatosis, depression, amyotrophic lateral sclerosis, arteriovenous malformations, cerebral aneurysms, dural arteriovenous fistulae, headaches, memory disorders, peripheral neuropathy, post-herpetic neuralgia, spinal cord tumors, strokes, and combinations thereof.
14. The use of claim 12, wherein the Tau-associated disease or disorder is dementia.
15. The use according to claim 12, wherein the Tau-associated disease or disorder is selected from the group consisting of subcortical dementia, frontotemporal dementia, dementia with lewy bodies, multi-infarct dementia, and semantic dementia.
16. The use of claim 12, wherein the Tau-associated disease or disorder is an autoimmune disease.
17. The use of claim 12, wherein the Tau-associated disease or disorder is alzheimer's disease.
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